Compounds for enhancing chemotherapy

ABSTRACT

The present invention provides 2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-ylamines, of the formula:  
                 
 
     or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , and R 7  are as defined herein. Also disclosed are pharmaceutical compositions comprising such compounds, and methods for using the compounds to increase the therapeutic efficacy of drugs.

[0001] This application is a divisional of U.S. patent application Ser.No. 09/822,743, filed Mar. 30, 2001, which claims priority from U.S.Provisional Application No. 60/193,109, filed Mar. 30, 2000 and U.S.Provisional Application No. 60/193,104, filed Mar. 30, 2000, thedisclosure of each of which is explicitly incorporated by referenceherein.

[0002] This invention was made with government support Grant CA64983awarded by the United States Public Health Service. The government hascertain rights in the invention.

BACKGROUND OF THE INVENTION

[0003] 1. Field of the Invention

[0004] This invention relates to chemical compounds, pharmaceuticalcompositions, and methods for increasing the therapeutic efficacy ofdrugs. Specifically, the invention relates to compounds andpharmaceutical compositions for inhibiting drug transport proteins thatefflux therapeutic agents from cells, and to methods for using thesecompounds and compositions to increase the efficacy of the therapeuticagents that are effluxed by these drug transport proteins.

[0005] 2. Background of the Invention

[0006] Eukaryotic cells possess integral membrane transport proteinswhich actively efflux a variety of chemical compounds from the cells(Gottesman and Pastan, 1993, Ann. Rev. Biochem. 62:385-427). In normalcells, these transport proteins serve to protect cells from cytotoxicand mutagenic compounds encountered in the diet or environment. However,these transport proteins are also very effective at removingpharmaceutical agents from target cells, thereby severely restrictingthe therapeutic efficacy of such agents. Consequently, compounds thatinhibit these transport proteins are expected to enhance the clinicalutility of drugs susceptible to such transport by enhancing drugaccumulation in target cells.

[0007] Two transport proteins, P-glycoprotein (P-gp) and multidrugresistance-associated protein (MRP), play important roles in thetreatment of human disease. Because of this involvement in humandisease, there is great interest in developing pharmaceutical agentsthat will effectively inhibit the function of these proteins. Morerecently, additional transport proteins have been identified, includingcMOAT and some proteins related to MRP.

[0008] An important issue regarding P-gp and MRP relates to theirsubstrate specificity. Pharmacological comparisons of cellsoverexpressing either P-gp or MRP demonstrate only a partial overlap ofthe resistance profiles conferred by these two proteins. For example,while MRP-transfected cells show a greater resistance to vincristine,etoposide, and doxorubicin, than to vinblastine and paclitaxel (Cole etal., 1994, Cancer Res. 54:5902-10), P-gp-transfected cells show a muchgreater resistance to vinblastine and paclitaxel (Smith et al., 1995,Cancer 75:2597-604). This differential pharmacology illustrates thefeasibility of developing selective inhibitors of these transporters,which should provide useful methods for increasing the therapeuticefficacy of many types of pharmaceutical agents.

[0009] Another significant difference between P-gp and MRP relates tothe distribution of these proteins in normal tissues. P-gp has beenshown to be expressed by several types of secretory cells, such ascapillary endothelial cells in the brain and testis, and at sites withinthe pancreas, kidney, and liver (Leveille-Webster and Arias, 1995, J.Membrane Biol. 143:89-102). In contrast, the expression of MRP mRNAoccurs in virtually every type of tissue (Zaman et al., 1993, CancerRes. 53:1747). Cells in various disease states also differentiallyexpress P-gp and MRP, indicating that selective inhibitors will bepreferred as therapeutic agents.

[0010] An example of transport protein-mediated drug resistance is thephenomenon of multidrug resistance (MDR), which is often encountered incancer chemotherapy (Gottesman and Pastan, 1993). As a result of thisphenomenon, tumor cells expressing transport proteins become resistantto many structurally unrelated drugs and the proliferation of resistanttumor cells results in the failure of chemotherapeutic treatment. Tumorcells from individuals undergoing chemotherapy often demonstrateelevated P-gp expression (Goldstein et al., 1989, J. Natl. Cancer Inst.81:116-24). Recent studies have also indicated that MRP is expressed ina high percentage of solid tumors and leukemias. However, no differencesin MRP levels were detected between normal and malignant hematopoieticcells (Abbaszadegan et al., 1994, Cancer Res. 54:4676-79), and MRPlevels were found to be lower in some tumors than in correspondingnormal tissues (Thomas et al., 1994, Eur. J. Cancer 30A: 1705-09).Therefore, it appears that different tumors display different patternsof expression of P-gp and MRP (and perhaps other transport proteins aswell).

[0011] Another example of drug transporter-mediated resistance isencountered in the effort to deliver drugs to the central nervoussystem, testes, and eye. In the brain, the blood-brain barrier exists toexclude toxic agents from the brain, and largely derives from the highlevel of expression of P-gp by endothelial cells in the capillaries ofthe brain (Schinkel et al., 1996, J. Clin. Invest. 97:2517-24). P-gp isalso highly expressed in the capillary endothelial cells of the eye(Holash and Stewart, 1993, Brain Res. 629:218-24) and testes (Holash etal., 1993, Proc. Natl. Acad. Sci. U.S.A. 90:11069-73), restricting theuptake of many compounds by these tissues. While these systems areuseful in protecting normal tissues, they also impair the delivery oftherapeutic agents to these sites when such delivery may be desired. Forexample, the expression of P-gp in brain capillary cells impairseffective treatment of brain tumors or neurological diseases using drugsthat are transported by P-gp. P-gp is also highly expressed in theliver, adrenal gland, and kidney (Lum and Gosland, 1995, Hematol. Oncol.Clin. North Amer. 9:319-36), other tissues in which drug delivery isrestricted. It is envisioned that inhibition of P-gp, or other transportproteins, will facilitate drug delivery to these sites and so enhancethe effectiveness of chemotherapy. It is also envisioned that drugtransport protein antagonists will be useful in suppressing thesecretion of endogenous compounds, including steroid hormones andcholesterol, providing therapeutic benefit under conditions in whichexcessive circulating levels of these compounds promote disease states.

[0012] Another example of drug transporter-mediated resistance isencountered in the effort to orally deliver therapeutic agents. The highexpression of P-gp at the brush-border membrane of the small intestinereduces the bioavailability of orally administered drugs subject totransport (Sparreboom et al., 1997, Proc. Natl. Acad. Sci. U.S.A.94:2031-35). It is envisioned that inhibition of P-gp, or othertransport proteins, will facilitate drug absorption, thereby enhancingthe effectiveness of chemotherapy.

[0013] Yet another example of drug transporter-mediated resistance isencountered in the effort to deliver therapeutic agents to certainleukocytes. P-gp is highly expressed by certain subtypes of lymphocytes,natural killer cells, and bone marrow stem cells (Gupta and Gollapudi,1993, J. Clin. Immunol. 13:289-301). This reduces the therapeuticefficacy of drugs targeting these cells, including anti-HIV compoundsfor the treatment of AIDS (Yusa et al., 1990, Biochem. Biophys. Res.Com. 169:986-90). Furthermore, the release of inflammatory cytokines andother immunomodulators appears to involve drug transporters (Salmon andDalton, 1996, J. Rheumatol. Suppl. 44:97-101). It is envisioned thatinhibition of P-gp, or other transport proteins, will facilitate drugaccumulation in these cells and so enhance the effectiveness ofchemotherapy.

[0014] Organisms other than mammals also possess transport proteinssimilar to P-gp that have been shown to confer resistance tochemotherapeutic agents (Ullman, 1995, J. Bioenergetics Biomembranes27:77-84). While the pharmacology of these transport proteins is notidentical to that of P-gp, certain modulators are able to inhibit drugtransport by both P-gp and for example, protozoan transport proteins(Frappier et al., 1996, Antimicrob. Agents Chemother. 40:1476-81). It isenvisioned that certain MDR modulators will facilitate drug accumulationin non-mammalian cells and so enhance the effectiveness ofanti-infection chemotherapy.

[0015] Since drug transport proteins are involved in determining thesuccess of chemotherapy in a variety of disease states, there is a needfor effective modulators of drug transport proteins. While a number ofcompounds have been shown to reverse transporter-mediated MDR in cellculture, the clinical success of these modulators has been unimpressive,predominantly due to their intrinsic toxicity and undesired effects onthe pharmacokinetics of accompanying drugs. However, the failure ofthese modulators can also be attributed to their lack of selectivity fordifferent drug transport proteins. For example, inhibition of MRP by MDRmodulators is likely to increase the uptake of cytotoxic anticancerdrugs by many normal tissues, thereby resulting in greater toxicity inthe individual. Successful chemotherapy will consequently require apanel of transporter antagonists with differential selectivity for P-gpand MRP that will allow selection of the appropriate sensitizing agent.Thus, there remains a need in the art to develop drug transport proteinmodulators that are selective for P-gp and MRP. The development of suchmodulators, and methods for their use, would have wide application inthe medical art.

SUMMARY OF THE INVENTION

[0016] The present invention provides chemical compounds, pharmaceuticalcompositions, and methods for increasing the therapeutic efficacy ofdrugs. Specifically, the invention provides compounds and pharmaceuticalcompositions for inhibiting drug transport proteins that effluxtherapeutic agents from cells, and to methods for using these compoundsand compositions to increase the efficacy of the therapeutic agents thatare effluxed by these drug transport proteins.

[0017] The present invention provides chemical compounds of the formula:

[0018] wherein

[0019] n is an integer from 1 to 12, preferably n is 1;

[0020] R₁ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferablypyridine, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, alkanoyl, —COOH, —CONH₂,—CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl) (C₁-C₆ alkyl), —SH, —S-alkyl,—CF₃, —OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, CSNH₂, —CSNH(C₁-C₆ alkyl), or —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl);

[0021] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0022] R₂ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferablypyridine, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, alkanoyl, —COOH, —CONH₂,—CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH, —S-alkyl, —CF₃,—OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl),;

[0023] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0024] R₃ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferablypyridine, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, alkanoyl, —COOH, —CONH₂,—CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH, —S-alkyl, —CF₃,—OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl);

[0025] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆); and

[0026] R₈ is H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;

[0027] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), alkoxy (C₁-C₆), halogen,haloalkyl, —CF₃, —OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH,—S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″ are independently H oralkyl (C₁-C₆); or pharmaceutically acceptable salts thereof.

[0028] The present invention also provides chemical compounds of theformula:

[0029] or a pharmaceutically acceptable salt thereof wherein,

[0030] R₁ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferablypyridine, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, alkanoyl, arylalkanoyl,—COOH, —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH,—S-alkyl, —CF₃, —OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl);

[0031] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0032] R₂ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl, halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl,—COOH, —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH,—S-alkyl, —CF₃, —OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl);

[0033] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆); or

[0034] R₂ is:

[0035] wherein R₄ represents H, alkyl (C₁-C₆), halogen, haloalkyl, —OH,alkoxy, hydroxyalkyl, —SH, —S-alkyl, —NO₂, —NH₂, mono- or dialkylamino,aminoalkyl, mono- or dialkylaminoalkyl, heterocycloalkyl, preferablypyrrolyl, morpholinyl, thiomorpholinyl, piperidyl, or piperazyl,heterocycloalkylalkyl, aryl, preferably phenyl, or arylalkyl, preferablybenzyl, heteroaryl, or heteroarylalkyl;

[0036] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0037] R₃ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl, halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl,—COOH, —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH,—S-alkyl, —CF₃, —OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl);

[0038] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0039] R₇ is H, alkyl (C₁-C₆), alkoxy, alkoxycarbonyl, preferablytertiary-butoxycarbonyl (BOC), arylalkyl, preferably benzyl, orarylalkoxycarbonyl, preferably carbobenzyloxy (Cbz), wherein each isoptionally substituted with up to three groups that are independentlyalkyl, alkoxy, —NO₂, —OH, halogen, —CN, —CF₃, or —OCF₃; and

[0040] R₈ is H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;

[0041] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), alkoxy (C₁-C₆), halogen,haloalkyl, —CF₃, —OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH,—S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″ are independently H oralkyl (C₁-C₆).

[0042] The present invention provides pharmaceutical compositionscomprising a compound of the formula:

[0043] or a pharmaceutically acceptable salt thereof; with at least onepharmaceutically acceptable carrier or excipient, wherein

[0044] n is an integer from 1 to 12, preferably n is 1;

[0045] R₁ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferablypyridine, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, alkanoyl, —COOH, —CONH₂,—CONH(C₁-C₆ alkyl), —CONH(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH, —S-alkyl,—CF₃, —OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl),;

[0046] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0047] R₂ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferablypyridine, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, alkanoyl, —COOH, —CONH₂,—CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH, —S-alkyl, —CF₃,—OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl);

[0048] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0049] R₃ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferablypyridine, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, alkanoyl, —COOH, —CONH₂,—CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH, —S-alkyl, —CF₃,—OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl);

[0050] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆); and

[0051] R₈ is H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;

[0052] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), alkoxy (C₁-C₆), halogen,haloalkyl, —CF₃, —OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH,—S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″ are independently H oralkyl (C₁-C₆).

[0053] The present invention also provides pharmaceutical compositionscomprising a compound of the formula:

[0054] or a pharmaceutically acceptable salt thereof; with at least onepharmaceutically acceptable carrier or excipient wherein,

[0055] R₁ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl, halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl,alkanoyl, arylalkanoyl, —COOH, —CONH₂, —CON(C₁-C₆ alkyl), —CONH(C₁-C₆alkyl)(C₁-C₆ alkyl), —SH, —S-alkyl, —CF₃, —OCF₃, —NO₂, —NH₂, —CO₂R₈,—OC(O)R₈, carbamoyl, mono or dialkylcarbamoyl, mono- or dialkylamino,aminoalkyl, mono- or dialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl),—CSN(C₁-C₆ alkyl)(C₁-C₆ alkyl);

[0056] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0057] R₂ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl, halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl,—COOH, —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH,—S-alkyl, —CF₃, —OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl);

[0058] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆); or

[0059] R₂ is:

[0060] wherein R₄ represents H, alkyl (C₁-C₆), halogen, haloalkyl, —OH,alkoxy, hydroxyalkyl, —SH, —S-alkyl, —NO₂, —NH₂, mono- or dialkylamino,aminoalkyl, mono- or dialkylaminoalkyl, heterocycloalkyl, preferablypyrrolyl, morpholinyl, thiomorpholinyl, piperidyl, or piperazyl,heterocycloalkylalkyl, aryl, preferably phenyl, or arylalkyl, preferablybenzyl, heteroaryl, or heteroarylalkyl;

[0061] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0062] R₃ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl, halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl,—COOH, —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH,—S-alkyl, —CF₃, —OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl);

[0063] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0064] R₇ is H, alkyl (C₁-C₆), alkoxy, alkoxycarbonyl, preferablytertiary-butoxycarbonyl (BOC), arylalkyl, preferably benzyl, orarylalkoxycarbonyl, preferably carbobenzyloxy (Cbz), wherein each isoptionally substituted with up to three groups that are independentlyalkyl, alkoxy, —NO₂, —OH, halogen, —CN, —CF₃, or —OCF₃; and

[0065] R₈ is H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;

[0066] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), alkoxy (C₁-C₆), halogen,haloalkyl, —CF₃, —OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH,—S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″ are independently H oralkyl (C₁-C₆).

[0067] The present invention provides methods for inhibiting drugtransport from target cells or tissues in an animal undergoingchemotherapy, comprising administering to the animal a pharmaceuticalcomposition of the present invention in an amount effective to inhibitdrug transport from the target cells or tissues of the animal. Thepresent invention also provides methods for preventing drug resistancein an animal undergoing chemotherapy, comprising administering to theanimal a pharmaceutical composition of the present invention in anamount effective to attenuate drug resistance. The methods of thepresent invention may be useful for treating MDR—by reversing MDR orchemosensitizing multidrug resistant cells to anti-cancer agents—orpreventing MDR.

[0068] The present invention further provides methods for enhancing thetherapeutic efficacy of an antiproliferative drug in target cells ortissues of an animal, comprising administering to the animal apharmaceutical composition of the present invention in an amounteffective to enhance delivery of the antiproliferative drug to thetarget cells or tissues of the animal.

[0069] The present invention still further provides methods forenhancing the therapeutic efficacy of an anti-infective agent in ananimal, comprising administering to the animal a pharmaceuticalcomposition of the present invention in an amount effective to inhibitdrug transport from an infectious agent in the animal.

[0070] The present invention still further provides methods forenhancing the delivery of a therapeutic agent to target cells or tissuesof an animal, comprising administering to the animal a pharmaceuticalcomposition of the present invention in an amount effective to enhancedelivery of the therapeutic agent to the target cells or tissues of theanimal. The methods of the present invention may be useful for enhancingthe delivery to target cells or tissues such as the brain, testes, eye,or leukocytes.

[0071] The present invention still further provides methods forenhancing the absorption of an orally-delivered therapeutic agent in ananimal, comprising administering to the animal a pharmaceuticalcomposition of the present invention in an amount effective to enhancedrug transport across the gastrointestinal tract.

[0072] The present invention provides a panel of novel drug transportinhibitors. The chemical compounds, pharmaceutical compositions, andmethods of the present invention provide important new therapeutic toolsfor treating or preventing a variety of diseases or conditions relatedto drug transport.

[0073] Specific preferred embodiments of the present invention willbecome evident from the following more detailed description of certainpreferred embodiments and the claims.

DESCRIPTION OF THE DRAWINGS

[0074]FIG. 1 illustrates one scheme for the synthesis of thephenoxymethylquinoxalinone compounds of the present invention;

[0075]FIG. 2 illustrates one scheme for the synthesis of thepyrroloquinoline compounds of the present invention;

[0076]FIG. 3 illustrates another scheme for the synthesis of thepyrroloquinoline compounds of the present invention;

[0077] FIGS. 4A-4B illustrate the antagonism of P-gp by verapamil andphenoxymethylquinoxalinone compounds;

[0078] FIGS. 5A-5B illustrate the lack of antagonism of MRP1 byphenoxymethylquinoxalinone compounds;

[0079]FIG. 6 illustrates another scheme for the synthesis of thepyrroloquinoline compounds of the present invention;

[0080]FIG. 7 illustrates the antagonism of P-gp by verapamil andpyrroloquinoline compounds;

[0081]FIG. 8 illustrates the lack of antagonism of MRP1 bypyrroloquinoline compounds;

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0082] The present invention provides chemical compounds, pharmaceuticalcompositions, and methods for increasing the therapeutic efficacy ofdrugs. The chemical compounds and pharmaceutical compositions of thepresent invention may be useful in preventing drug resistance orinhibiting drug transport in an animal undergoing chemotherapy,enhancing the therapeutic efficacy of an antiproliferative drug or ananti-infective agent in an animal, enhancing the delivery of atherapeutic agent in an animal, or enhancing the absorption of anorally-delivered therapeutic agent in an animal.

[0083] The term “alkoxy” represents an alkyl group of indicated numberof carbon atoms attached to the parent molecular moiety through anoxygen bridge. Examples of alkoxy groups include, for example, methoxy,ethoxy, propoxy and isopropoxy.

[0084] The term “alkyl” includes those alkyl groups of a designed numberof carbon atoms. Alkyl groups may be straight, or branched. Examples of“alkyl” include methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- andtert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, and the like.

[0085] The term “aryl” refers to an aromatic hydrocarbon ring systemcontaining at least one aromatic ring. The aromatic ring may optionallybe fused or otherwise attached to other aromatic hydrocarbon rings ornon-aromatic hydrocarbon rings. Examples of aryl groups include, forexample, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene and biphenyl.Preferred examples of aryl groups include phenyl and naphthyl.

[0086] The term “cycloalkyl” refers to a C₃-C₈ cyclic hydrocarbon.Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

[0087] The term “cycloalkylalkyl,” as used herein, refers to a C₃-C₇cycloalkyl group attached to the parent molecular moiety through analkyl group, as defined above. Examples of cycloalkylalkyl groupsinclude cyclopropylmethyl and cyclopentylethyl.

[0088] The terms “halogen” or “halo” indicate fluorine, chlorine,bromine, or iodine.

[0089] The term “heterocycloalkyl,” refers to a non-aromatic ring systemcontaining at least one heteroatom selected from nitrogen, oxygen, andsulfur. The heterocycloalkyl ring may be optionally fused to orotherwise attached to other heterocycloalkyl rings and/or non-aromatichydrocarbon rings. Preferred heterocycloalkyl groups have from 3 to 7members. Examples of heterocycloalkyl groups include, for example,piperazine, morpholine, piperidine, tetrahydrofuran, pyrrolidine, andpyrazole. Preferred heterocycloalkyl groups include piperidinyl,piperazinyl, morpholinyl, and pyrolidinyl.

[0090] The term “heteroaryl” refers to an aromatic ring systemcontaining at least one heteroatom selected from nitrogen, oxygen, andsulfur. The heteroaryl ring may be fused or otherwise attached to one ormore heteroaryl rings, aromatic or non-aromatic hydrocarbon rings orheterocycloalkyl rings. Examples of heteroaryl groups include, forexample, pyridine, furan, thiophene, 5,6,7,8-tetrahydroisoquinoline andpyrimidine. Preferred examples of heteroaryl groups include thienyl,benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl,benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl,isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl,tetrazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl.

[0091] In certain situations, the compounds of this invention maycontain one or more asymmetric carbon atoms, so that the compounds canexist in different stereoisomeric forms. These compounds can be, forexample, racemates, chiral non-racemic or diastereomers. In thesesituations, the single enantiomers, i.e., optically active forms, can beobtained by asymmetric synthesis or by resolution of the racemates.Resolution of the racemates can be accomplished, for example, byconventional methods such as crystallization in the presence of aresolving agent; chromatography, using, for example a chiral HPLCcolumn; or derivatizing the racemic mixture with a resolving reagent togenerate diastereomers, separating the diastereomers via chromatography,and removing the resolving agent to generate the original compound inenantiomerically enriched form. Any of the above procedures can berepeated to increase the enantiomeric purity of a compound.

[0092] When the compounds described herein contain olefinic double bondsor other centers of geometric asymmetry, and unless otherwise specified,it is intended that the compounds include the cis, trans, Z- andE-configurations. Likewise, all tautomeric forms are also intended to beincluded.

[0093] In one embodiment, the chemical compound of the present inventionis a compound of the formula:

[0094] or a pharmaceutically acceptable salt thereof wherein,

[0095] n is an integer from 1 to 12, preferably n is 1;

[0096] R₁ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferablypyridine, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, alkanoyl, —COOH, —CONH₂,—CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH, —S-alkyl, —CF₃,—OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl);

[0097] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0098] R₂ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferablypyridine, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, alkanoyl, —COOH, —CONH₂,—CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH, —S-alkyl, —CF₃,—OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl);

[0099] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0100] R₃ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferablypyridine, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, alkanoyl, —COOH, —CONH₂,—CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH, —S-alkyl, —CF₃,—OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl);

[0101] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆); and

[0102] R₈ is H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;

[0103] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), alkoxy (C₁-C₆), halogen,haloalkyl, —CF₃, —OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH,—S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″ are independently H oralkyl (C₁-C₆).

[0104] Non-toxic pharmaceutically acceptable salts of the compounds ofthe present invention include, but are not limited to salts of inorganicacids such as hydrochloric, sulfuric, phosphoric, diphosphoric,hydrobromic, and nitric or salts of organic acids such as formic,citric, malic, maleic, fumaric, tartaric, succinic, acetic, lactic,methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic, salicylicand stearic. Similarly, pharmaceutically acceptable cations include, butare not limited to sodium, potassium, calcium, aluminum, lithium andammonium. Those skilled in the art will recognize a wide variety ofnon-toxic pharmaceutically acceptable addition salts. The invention alsoencompasses prodrugs of the compounds of the present invention.

[0105] The invention also encompasses the acylated prodrugs of thecompounds of the present invention. Those skilled in the art willrecognize various synthetic methodologies, which may be employed toprepare non-toxic pharmaceutically acceptable addition salts andacylated prodrugs of the compounds encompassed by the present invention.

[0106] In a more preferred embodiment, compound (I) is defined suchthat:

[0107] n is an integer from 1 to 6;

[0108] R₁, and R₃ are independently H, alkyl (C₁-C₁₅), cycloalkyl,cycloalkylalkyl, aryl, preferably phenyl, arylalkyl, preferably benzyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, alkanoyl, —CONH₂,—CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —CF₃, —OCF₃, —NO₂,—NH₂, —CO₂R₈, —OC(O)R₈, mono- or dialkylamino, aminoalkyl, or mono- ordialkylaminoalkyl;

[0109] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, or —NR′R″, wherein R′ and R″ areindependently H or alkyl (C₁-C₆);

[0110] R₂ is H, alkyl (C₁-C₈), cycloalkyl, cycloalkylalkyl, aryl,preferably phenyl, arylalkyl, preferably benzyl, halogen, haloalkyl,—OH, alkoxy, hydroxyalkyl, alkanoyl, —CONH₂, —CONH(C₁-C₆ alkyl),—CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, or mono- ordialkylaminoalkyl;

[0111] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, or —NR′R″, wherein R′ and R″ areindependently H or alkyl (C₁-C₆); and

[0112] R₈ is H, alkyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;

[0113] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), alkoxy (C₁-C₆), halogen,—CF₃, —OCF₃, —OH, hydroxyalkyl, —CN, —CO₂H, or —NR′R″, wherein R′ and R″are independently H or alkyl (C₁-C₆).

[0114] In another preferred embodiment, compound (I) is defined suchthat:

[0115] n is 1;

[0116] R₁ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,preferably phenyl, arylalkyl, preferably benzyl, halogen, haloalkyl,—OH, alkoxy, hydroxyalkyl, alkanoyl, —CONH₂, —CONH(C₁-C₆ alkyl),—CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —CF₃, —OCF₃, —NO₂, —NH₂, —CO₂R₈,—OC(O)R₈, mono- or dialkylamino, aminoalkyl, or mono- ordialkylaminoalkyl;

[0117] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, or —NR′R″, wherein R′ and R″ areindependently H or alkyl (C₁-C₆);

[0118] R₂ is H, alkyl (C₁-C₈), cycloalkyl, cycloalkylalkyl, aryl,preferably phenyl, arylalkyl, preferably benzyl, halogen, haloalkyl,—OH, alkoxy, hydroxyalkyl, alkanoyl, —CONH₂, —CONH(C₁-C₆ alkyl),—CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, or mono- ordialkylaminoalkyl;

[0119] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, or —NR′R″, wherein R′ and R″ areindependently H or alkyl (C₁-C₆);

[0120] R₃ is H, alkyl (C₁-C₆), alkoxy, halogen, alkanoyl, —CF₃, or—OCF₃; and

[0121] R₈ is alkyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;

[0122] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), alkoxy (C₁-C₆), halogen,—CF₃, —OCF₃, —OH, hydroxyalkyl, —CN, —CO₂H, or —NR′R″, wherein R′ and R″are independently H or alkyl (C₁-C₆).

[0123] Preferred embodiments of the phenoxymethylquinoxalinone compoundsof the present invention include 1,3-Dimethyl-1H-quinoxalin-2-one;1-Methyl-3-phenoxymethyl-1H-quinoxalin-2-one;3-(4-Cyano-phenoxymethyl)-1-methyl-1H-quinoxalin-2-one;3-(3-tert-Butyl-phenoxymethyl)-1-methyl-1H-quinoxalin-2-one;3-(4-Benzoyl-phenoxymethyl)-1-methyl-1H-quinoxalin-2-one;3-Methoxy-4-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl-methoxy)-benzoylmethyl ester;2-(4-Methyl-3-oxo-3,4-dihydroquinoxalin-2-yl-methoxy)-N-phenylbenzamide;4-(4-Methyl-3-oxo-3,4-dihydro-quinoxalin-2-ylmethoxy)-benzoyl ethylester;2-(4-Benzyl-3-oxo-3,4-dihydroquinoxalin-2-ylmethoxy)-N-phenylbenzamide;or pharmaceutically acceptable salts thereof.

[0124] Particularly preferred embodiments of thephenoxymethylquinoxalinone compounds of the present invention include2-(4-Methyl-3-oxo-3,4-dihydroquinoxalin-2-yl-methoxy)-N-phenylbenzamideand2-(4-Benzyl-3-oxo-3,4-dihydroquinoxalin-2-ylmethoxy)-N-phenyl-benzamide.

[0125] The phenoxymethylquinoxalinone compounds of the present inventionmay be synthesized according to reaction scheme shown in FIG. 1. Thereactions as shown in FIG. 1 will occur with a wide variety ofR₁-substituted phenols and virtually any R₂- and R₃-substituteddiaminobenzene compound, allowing the rapid synthesis of very diversefamilies of phenoxymethylquinoxalinone compounds. A large number ofstarting materials are available from Aldrich Chemical Company and otherchemical suppliers.

[0126] In another embodiment, the chemical compound of the presentinvention is a pyrroloquinoline of the formula:

[0127] or a pharmaceutically acceptable salt thereof, wherein

[0128] R₁ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl, halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl,alkanoyl, arylalkanoyl, —COOH, —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆alkyl)(C₁-C₆ alkyl), —SH, —S-alkyl, —CF₃, —OCF₃, —NO₂, —NH₂, —CO₂R₈,—OC(O)R₈, carbamoyl, mono or dialkylcarbamoyl, mono- or dialkylamino,aminoalkyl, mono- or dialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl),—CSN(C₁-C₆ alkyl)(C₁-C₆ alkyl);

[0129] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0130] R₂ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl, haloalkyl, —OH, alkoxy, hydroxyalkyl, —COOH,—CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —NH₂,—CO₂R₈, —OC(O)R₈, carbamoyl, mono or dialkylcarbamoyl, mono- ordialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, —CSNH₂,—CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆ alkyl),;

[0131] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆); or

[0132] R₂ is:

[0133] wherein R₄ represents H, alkyl (C₁-C₆), halogen, haloalkyl, —OH,alkoxy, hydroxyalkyl, —SH, —S-alkyl, —NO₂, —NH₂, mono- or dialkylamino,aminoalkyl, mono- or dialkylaminoalkyl, heterocycloalkyl, preferablypyrrolyl, morpholinyl, thiomorpholinyl, piperidyl, or piperazyl,heterocycloalkylalkyl, aryl, preferably phenyl, or arylalkyl, preferablybenzyl, heteroaryl, or heteroarylalkyl;

[0134] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0135] R₃ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl, halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl,—COOH, —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH,—S-alkyl, —CF₃, —OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl);

[0136] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0137] R₇ is H, alkyl (C₁-C₆), alkoxy, alkoxycarbonyl, preferablytertiary-butoxycarbonyl (BOC), arylalkyl, preferably benzyl, orarylalkoxycarbonyl, preferably carbobenzyloxy (Cbz), wherein each isoptionally substituted with up to three groups that are independentlyalkyl, alkoxy, —NO₂, —OH, halogen, —CN, —CF₃, or —OCF₃; and

[0138] R₈ is H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;

[0139] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), alkoxy (C₁-C₆), halogen,haloalkyl, —CF₃, —OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH,—S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″ are independently H oralkyl (C₁-C₆).

[0140] In a preferred embodiment, the pyrroloquinoline compound of thepresent invention is of the formula:

[0141] or a pharmaceutically acceptable salt thereof, wherein

[0142] R₁ is H, alkyl (C₁-C₆), alkoxy, cycloalkyl, cycolalkylalkyl,alkanoyl, benzyl, or benzoyl;

[0143] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —OH,alkoxy, hydroxyalkyl, —SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″are independently H or alkyl (C₁-C₆);

[0144] R₂ is H, alkyl (C₁-C₆), cycloalkyl, cycolalkylalkyl, arylalkyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, —CONH₂, —CONH(C₁-C₆alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), aminoalkyl, mono- ordialkylaminoalkyl, phenyl, or benzyl;

[0145] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —OH,alkoxy, hydroxyalkyl, —SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″are independently H or alkyl (C₁-C₆); or

[0146] R₂ is:

[0147] wherein

[0148] R₄ represents H, alkyl (C₁-C₆), halogen, haloalkyl, —OH, alkoxy,hydroxyalkyl, —SH, —S-alkyl, —NO₂, —NH₂, mono- or dialkylamino,aminoalkyl, mono- or dialkylamino, pyrrolyl, piperidyl, piperazyl,phenyl, or benzyl;

[0149] wherein each of the above is optionally substituted with up to 4groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —OH,alkoxy, hydroxyalkyl, —SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″are independently H or alkyl (C₁-C₆);

[0150] R₃ is H, alkyl (C₁-C₁₅), cycloalkyl, cycolalkylalkyl, halogen,haloalkyl, —OH, alkoxy, hydroxyalkyl, —CONH₂, —CONH(C₁-C₆ alkyl),—CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —CO₂R₈, —CF₃, —OCF₃, —NO₂, —NH₂,aminoalkyl, mono- or dialkylaminoalkyl, phenyl, or benzyl;

[0151] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —OH,alkoxy, hydroxyalkyl, —SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″are H or alkyl (C₁-C₆);

[0152] R₇ is H, alkyl (C₁-C₆), alkoxy, alkoxycarbonyl, preferablytertiary-butoxycarbonyl (BOC), arylalkyl, preferably benzyl, orarylalkoxycarbonyl, preferably carbobenzyloxy (Cbz), wherein each isoptionally substituted with up to three groups that are independentlyalkyl, alkoxy, —NO₂, —OH, halogen, —CN, —CF₃, or —OCF₃; and

[0153] R₈ is H, alkyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;

[0154] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), alkoxy (C₁-C₆), halogen,haloalkyl, —CF₃, —OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH,—S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″ are independently H oralkyl (C₁-C₆).

[0155] In a particularly preferred embodiment, the pyrroloquinoline ofthe present invention is defined as:

[0156] or pharmaceutically acceptable salts thereof, wherein,

[0157] R₄ is H, alkyl (C₁-C₆), halogen, haloalkyl, —OH, alkoxy,hydroxyalkyl, —SH, —S-alkyl, —NO₂, —NH₂, mono- or dialkylamino,aminoalkyl, mono- or dialkylamino, phenyl, or benzyl;

[0158] wherein each of the above is optionally substituted with up to 4groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —OH,alkoxy, hydroxyalkyl, —NO₂, or —NR′R″, wherein R′ and R″ areindependently H or alkyl (C₁-C₆);

[0159] R₃ is H, alkyl (C₁-C₄), halogen, alkoxy (C₁-C₄), —CF₃, or —OCF₃;

[0160] R₅ is H, alkyl (C₁-C₄), halogen, alkoxy (C₁-C₄), —CF₃, or —OCF₃;and

[0161] R₇ is H, alkyl (C₁-C₆), alkoxy, alkoxycarbonyl, preferablytertiary-butoxycarbonyl (BOC), arylalkyl, preferably benzyl, orarylalkoxycarbonyl, preferably carbobenzyloxy (Cbz), wherein each isoptionally substituted with up to three groups that are independentlyalkyl, alkoxy, —NO₂, —OH, halogen, —CN, —CF₃, or —OCF₃.

[0162] More preferred embodiments of the pyrroloquinoline compounds ofthe present invention include(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-ylamino)-acetic acidethyl ester; (1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-(3,5-dimethoxy-benzyl)-amine;N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2-piperidin-1-yl-acetamide;N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2-phenyl-acetamide;N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2-fluoro-6-trifluoromethyl-benzamide;N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-4-fluoro-3-trifluoromethyl-benzamide;N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2,3,6-trifluoro-benzamide;or pharmaceutically acceptable salts thereof.

[0163] The pyrroloquinoline compounds of the present invention may besynthesized according to reaction scheme shown in FIG. 2. In thisreaction scheme, a 2,4-dichloro-3-(β-chloroethyl) quinoline derivative,which may be prepared by treatment of the corresponding derivative of2,3,4,5-tetrahydro-4-oxofuro[3,2-c]quinoline with phosphorusoxychloride, can be reacted with a compound containing a primary amineto form the substituted pyrrolo[2,3-b]quinoline nucleus (Tanaka et al.,1972, Chem. Pham. Bull. 20:109). Reaction with ammonia can producesubstituted amino-pyrrolo[2,3-b]quinoline, which can be further reactedwith carboxylate compounds to form the amide linkage indicated in FIG.2. These reactions will occur with virtually any R₁-substituted primaryamine and virtually any R₄-substituted carboxylate compound, allowingthe rapid synthesis of very diverse families of pyrroloquinolinederivatives. A large number of starting materials are available fromAldrich Chemical Company and other chemical suppliers.

[0164] The pyrroloquinoline compounds of the present invention may alsobe synthesized according to reaction scheme shown in FIG. 3. In thisreaction scheme, R₁-substituted pyrrolidinone can be reacted withphosphorus oxychloride, followed by reaction withR₃-substituted-2-cyanoaniline (European Patent Serial No. EP 430 485 toKuroki et al.). Treatment with acid or base allows cyclization to thesubstituted amino pyrrolo[2,3-b]quinoline that can be furtherderivatized as shown in FIG. 2.

[0165] The chemical compounds of the present invention may be formulatedinto compositions with a biologically compatible vehicle or carrier.Such compositions may further comprise an additionaltransport-inhibiting compound or an additional therapeutic agent.

[0166] In one embodiment, the pharmaceutical compositions of the presentinvention comprise a phenoxymethylquinoxalinone compound (I) of theformula:

[0167] or a pharmaceutically acceptable salt thereof; with at least onepharmaceutically acceptable carrier or excipient, wherein

[0168] n is an integer from 1 to 12, preferably n is 1;

[0169] R₁ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferablypyridine, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, alkanoyl, —COOH, —CONH₂,—CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH, —S-alkyl, —CF₃,—OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl);

[0170] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0171] R₂ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferablypyridine, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, alkanoyl, —COOH, —CONH₂,—CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH, —S-alkyl, —CF₃,—OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl);

[0172] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0173] R₃ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferablypyridine, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, alkanoyl, —COOH, —CONH₂,—CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH, —S-alkyl, —CF₃,—OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl);

[0174] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆); and

[0175] R₈ is H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;

[0176] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), alkoxy (C₁-C₆), halogen,haloalkyl, —CF₃, —OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH,—S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″ are independently H oralkyl (C₁-C₆).

[0177] In a more preferred embodiment, the pharmaceutical compositionsof the present invention comprise a phenoxymethylquinoxalinone compoundsof formula (I) wherein:

[0178] n is an integer from 1 to 6;

[0179] R₁ and R₃ are independently H, alkyl (C₁-C₁₅), cycloalkyl,cycloalkylalkyl, aryl, preferably phenyl, arylalkyl, preferably benzyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, alkanoyl, —CONH₂,—CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —CF₃, —OCF₃, —NO₂,—NH₂, —CO₂R₈, —OC(O)R₈, mono- or dialkylamino, aminoalkyl, or mono- ordialkylaminoalkyl;

[0180] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, or —NR′R″, wherein R′ and R″ areindependently H or alkyl (C₁-C₆);

[0181] R₂ is H, alkyl (C₁-C₈), cycloalkyl, cycloalkylalkyl, aryl,preferably phenyl, arylalkyl, preferably benzyl, halogen, haloalkyl,—OH, alkoxy, hydroxyalkyl, alkanoyl, —CONH₂, —CONH(C₁-C₆ alkyl),—CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, or mono- ordialkylaminoalkyl;

[0182] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, or —NR′R″, wherein R′ and R″ areindependently H or alkyl (C₁-C₆); and

[0183] R₈ is H, alkyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;

[0184] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), alkoxy (C₁-C₆), halogen,—CF₃, —OCF₃, —OH, hydroxyalkyl, —CN, —CO₂H, or —NR′R″, wherein R′ and R″are independently H or alkyl (C₁-C₆).

[0185] In another more preferred embodiment, the pharmaceuticalcompositions of the present invention comprise aphenoxymethylquinoxalinone compound of the formula:

[0186] or a pharmaceutically acceptable salt thereof, wherein

[0187] R₁ and R₃ are independently H, alkyl (C₁-C₁₅), cycloalkyl,cycloalkylalkyl, aryl, preferably phenyl, arylalkyl, preferably benzyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, alkanoyl, —CONH₂,—CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —CF₃, —OCF₃, —NO₂,—NH₂, —CO₂R₈, —OC(O)R₈, mono- or dialkylamino, aminoalkyl, or mono- ordialkylaminoalkyl;

[0188] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, or —NR′R″, wherein R′ and R″ areindependently H or alkyl (C₁-C₆);

[0189] R₂ is H, alkyl (C₁-C₈), cycloalkyl, cycloalkylalkyl, aryl,preferably phenyl, arylalkyl, preferably benzyl, halogen, haloalkyl,—OH, alkoxy, hydroxyalkyl, alkanoyl, —CONH₂, —CONH(C₁-C₆ alkyl),—CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, or mono- ordialkylaminoalkyl;

[0190] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, or —NR′R″, wherein R′ and R″ areindependently H or alkyl (C₁-C₆); and

[0191] R₈ is H, alkyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;

[0192] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), alkoxy (C₁-C₆), halogen,—CF₃, —OCF₃, —OH, hydroxyalkyl, —CN, —CO₂H, or —NR′R″, wherein R′ and R″are independently H or alkyl (C₁-C₆).

[0193] An even more preferred embodiment of the pharmaceuticalcompositions of the present invention comprise1,3-Dimethyl-1H-quinoxalin-2-one;1-Methyl-3-phenoxymethyl-1H-quinoxalin-2-one;3-(4-Cyano-phenoxymethyl)-1-methyl-1H-quinoxalin-2-one;3-(3-tert-Butyl-phenoxymethyl)-1-methyl-1H-quinoxalin-2-one;3-(4-Benzoyl-phenoxymethyl)-1-methyl-1H-quinoxalin-2-one;3-Methoxy-4-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl-methoxy)-benzoylmethyl ester;2-(4-Methyl-3-oxo-3,4-dihydroquinoxalin-2-yl-methoxy)-N-phenylbenzamide;4-(4-Methyl-3-oxo-3,4-dihydro -quinoxalin-2-ylmethoxy)-benzoyl ethylester;2-(4-Benzyl-3-oxo-3,4-dihydroquinoxalin-2-ylmethoxy)-N-phenylbenzamide;or pharmaceutically acceptable salts thereof; with at least onepharmaceutically acceptable carrier or excipient.

[0194] Particularly preferred embodiments of the pharmaceuticalcompositions of the present invention comprise2-(4-Methyl-3-oxo-3,4-dihydroquinoxalin-2-yl-methoxy)-N-phenyl-benzamideor2-(4-Benzyl-3-oxo-3,4-dihydroquinoxalin-2-ylmethoxy)-N-phenylbenzamide;with at least one pharmaceutically acceptable carrier or excipient.

[0195] In another embodiment, the pharmaceutical compositions of thepresent invention comprise a compound of the formula:

[0196] or a pharmaceutically acceptable salt thereof; with at least onepharmaceutically acceptable carrier or excipient, wherein

[0197] R₁ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl, halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl,alkanoyl, arylalkanoyl, —COOH, —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆alkyl)(C₁-C₆ alkyl), —SH, —S-alkyl, —CF₃, —OCF₃, —NO₂, —NH₂, —CO₂R₈,—OC(O)R₈, carbamoyl, mono or dialkylcarbamoyl, mono- or dialkylamino,aminoalkyl, mono- or dialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl),—CSN(C₁-C₆ alkyl)(C₁-C₆ alkyl);

[0198] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0199] R₂ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl, halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl,—COOH, —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH,—S-alkyl, —CF₃, —OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSONH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl);

[0200] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆); or

[0201] R₂ is:

[0202] wherein R₄ represents H, alkyl (C₁-C₆), halogen, haloalkyl, —OH,alkoxy, hydroxyalkyl, —SH, —S-alkyl, —NO₂, —NH₂, mono- or dialkylamino,aminoalkyl, mono- or dialkylaminoalkyl, heterocycloalkyl, preferablypyrrolyl, morpholinyl, thiomorpholinyl, piperidyl, or piperazyl,heterocycloalkylalkyl, aryl, preferably phenyl, or arylalkyl, preferablybenzyl, heteroaryl, or heteroarylalkyl;

[0203] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0204] R₃ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl, halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl,—COOH, —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH,—S-alkyl, —CF₃, —OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl);

[0205] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);

[0206] R₇ is H, alkyl (C₁-C₆), alkoxy, alkoxycarbonyl, preferablytertiary-butoxycarbonyl (BOC), arylalkyl, preferably benzyl, orarylalkoxycarbonyl, preferably carbobenzyloxy (Cbz), wherein each isoptionally substituted with up to three groups that are independentlyalkyl, alkoxy, —NO₂, —OH, halogen, —CN, —CF₃, or —OCF₃; and

[0207] R₈ is H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;

[0208] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), alkoxy (C₁-C₆), halogen,haloalkyl, —CF₃, —OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH,—S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″ are independently H oralkyl (C₁-C₆).

[0209] In a preferred embodiment, the pharmaceutical compositions of thepresent invention comprise a pyrroloquinoline compound of the formula:

[0210] with at least one pharmaceutically acceptable carrier orexcipient, wherein

[0211] R₁ is H, alkyl (C₁-C₆), alkoxy, cycloalkyl, cycloalkylalkyl,alkanoyl, benzyl, or benzoyl;

[0212] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —OH,alkoxy, hydroxyalkyl, —SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″are independently H or alkyl (C₁-C₆);

[0213] R₂ is H, alkyl (C₁-C₆), cycloalkyl, cycloalkylalkyl, arylalkyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, —CONH₂, —CONH(C₁-C₆alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), aminoalkyl, mono- ordialkylaminoalkyl, phenyl, or benzyl;

[0214] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —OH,alkoxy, hydroxyalkyl, —SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″are independently H or alkyl (C₁-C₆); or

[0215] R₂ is:

[0216] wherein

[0217] R₄ represents H, alkyl (C₁-C₆), halogen, haloalkyl, —OH, alkoxy,hydroxyalkyl, —SH, —S-alkyl, —NO₂, —NH₂, mono- or dialkylamino,aminoalkyl, mono- or dialkylaminoalkyl, pyrrolyl, piperidyl, piperazyl,phenyl, or benzyl;

[0218] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —OH,alkoxy, hydroxyalkyl, —SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″are independently H or alkyl (C₁-C₆);

[0219] R₃ is H, alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, halogen,haloalkyl, —OH, alkoxy, hydroxyalkyl, —CONH₂, —CONH(C₁-C₆ alkyl),—CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —CO₂R₈, —CF₃, —OCF₃, —NO₂, —NH₂,aminoalkyl, mono- or dialkylaminoalkyl, phenyl, or benzyl;

[0220] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —OH,alkoxy, hydroxyalkyl, —SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″are H or alkyl (C₁-C₆);

[0221] R₇ is H, alkyl (C₁-C₆), alkoxy, alkoxycarbonyl, preferablytertiary-butoxycarbonyl (BOC), arylalkyl, preferably benzyl, orarylalkoxycarbonyl, preferably carbobenzyloxy (Cbz), wherein each isoptionally substituted with up to three groups that are independentlyalkyl, alkoxy, —NO₂, —OH, halogen, —CN, —CF₃, or —OCF₃; and

[0222] R₈ is H, alkyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;

[0223] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), alkoxy (C₁-C₆), halogen,haloalkyl, —CF₃, —OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH,—S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″ are independently H oralkyl (C₁-C₆).

[0224] In a particularly preferred embodiment, the pharmaceuticalcompositions of the present invention comprise a pyrroloquinolinecompound of the formula:

[0225] or a pharmaceutically acceptable salt thereof; with at least onepharmaceutically acceptable carrier or excipient wherein

[0226] R₄ represents H, alkyl (C₁-C₆), halogen, haloalkyl, —OH, alkoxy,hydroxyalkyl, —SH, —S-alkyl, —NO₂, —NH₂, mono- or dialkylamino,aminoalkyl, mono- or dialkylamino, pyrrolyl, piperidyl, piperazyl,phenyl, or benzyl;

[0227] wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —OH,alkoxy, hydroxyalkyl, —SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″are independently H or alkyl (C₁-C₆);

[0228] R₃ is H, alkyl (C₁-C₄), halogen, alkoxy (C₁-C₄), —CF₃, or —OCF₃;

[0229] R₅ is H, alkyl (C₁-C₄), halogen, alkoxy (C₁-C₄), —CF₃, or —OCF₃;and

[0230] R₇ is H, alkyl (C₁-C₆), alkoxy, alkoxycarbonyl, preferablytertiary-butoxycarbonyl (BOC), arylalkyl, preferably benzyl, orarylalkoxycarbonyl, preferably carbobenzyloxy (Cbz), wherein each isoptionally substituted with up to three groups that are independentlyalkyl, alkoxy, —NO₂, —OH, halogen, —CN, —CF₃, or —OCF₃.

[0231] More preferred embodiments of these pharmaceutical compositionscomprise(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-ylamino)-acetic acidethyl ester; (1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-(3,5-dimethoxy-benzyl)-amine;N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2-piperidin-1-yl-acetamide;N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2-phenyl-acetamide;N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2-fluoro-6-trifluoromethyl-benzamide;N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-4-fluoro-3-trifluoromethyl-benzamide;N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2,3,6-trifluoro-benzamide;or pharmaceutically acceptable salts thereof; with at least onepharmaceutically acceptable carrier or excipient.

[0232] Pharmaceutically acceptable salts of the chemical compounds ofthe present invention, which also have chemosensitizing activity (e.g.,the hydrochloride or sodium salts), may be prepared following proceduresthat are familiar to those skilled in the art.

[0233] The chemosensitizing pharmaceutical compositions of the presentinvention comprise one or more of the chemical compounds of the presentinvention, as active ingredients, in combination with a pharmaceuticallyacceptable carrier, medium, or auxiliary agent.

[0234] The pharmaceutical compositions of the present invention may beprepared in various forms for administration, including tablets,caplets, pills or dragees, or can be filled in suitable containers, suchas capsules, or, in the case of suspensions, filled into bottles. Asused herein “pharmaceutically acceptable carrier medium” includes anyand all solvents, diluents, or other liquid vehicle; dispersion orsuspension aids; surface active agents; preservatives; solid binders;lubricants and the like, as suited to the particular dosage formdesired. Various vehicles and carriers used in formulatingpharmaceutical compositions and known techniques for the preparationthereof are disclosed in Remington's Pharmaceutical Sciences (A. Osol etal. eds., 15th ed. 1975). Except insofar as any conventional carriermedium is incompatible with the chemical compounds of the presentinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any other componentof the pharmaceutical composition, the use of the carrier medium iscontemplated to be within the scope of this invention.

[0235] In the pharmaceutical compositions of the present invention, theactive agent may be present in an amount of at least 1% and not morethan 95% by weight, based on the total weight of the composition,including carrier medium or auxiliary agents. Preferably, the proportionof active agent varies between 1% to 70% by weight of the composition.Pharmaceutical organic or inorganic solid or liquid carrier mediasuitable for enteral or parenteral administration can be used to make upthe composition. Gelatin, lactose, starch, magnesium, stearate, talc,vegetable and animal fats and oils, gum polyalkylene glycol, or otherknown excipients or diluents for medicaments may all be suitable ascarrier media.

[0236] The pharmaceutical compositions of the present invention may beadministered using any amount and any route of administration effectivefor increasing the therapeutic efficacy of drugs. Thus the expression“therapeutically effective amount,” as used herein, refers to asufficient amount of the chemosensitizing agent to provide the desiredeffect against target cells. The exact amount required will vary fromsubject to subject, depending on the species, age, and general conditionof the subject; the particular chemosensitizing agent; its mode ofadministration; and the like.

[0237] The pharmaceutical compounds of the present invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. “Dosage unit form,” as used herein, refers to aphysically discrete unit of therapeutic agent appropriate for the animalto be treated. Each dosage should contain the quantity of activematerial calculated to produce the desired therapeutic effect either assuch, or in association with the selected pharmaceutical carrier medium.Typically, the pharmaceutical composition will be administered in dosageunits containing from about 0.1 mg to about 10,000 mg of the agent, witha range of about 1 mg to about 1000 mg being preferred.

[0238] The pharmaceutical compositions of the present invention may beadministered orally or paternally, such as by intramuscular injection,intraperitoneal injection, or intravenous infusion. The pharmaceuticalcompositions may be administered orally or parenterally at dosage levelsof about 0.1 to about 1000 mg/kg, and preferably from about 1 to about100 mg/kg, of animal body weight per day, one or more times a day, toobtain the desired therapeutic effect.

[0239] Although the pharmaceutical compositions of the present inventioncan be administered to any subject that can benefit from the therapeuticeffects of the compositions, the compositions are intended particularlyfor the treatment of diseases in humans.

[0240] The pharmaceutical compositions of the present invention willtypically be administered from 1 to 4 times a day, so as to deliver thedaily dosage as described herein. Alternatively, dosages within theseranges can be administered by constant infusion over an extended periodof time, usually 1 to 96 hours, until the desired therapeutic benefitshave been obtained. However, the exact regimen for administration of thechemical compounds and pharmaceutical compositions described herein willnecessarily be dependent on the needs of the animal being treated, thetype of treatments being administered, and the judgment of the attendingphysician.

[0241] The pharmaceutical compositions of the present invention can beused in various protocols for treating animals. In one embodiment of themethods of the present invention, drug transport from target cells ortissues in an animal undergoing chemotherapy is inhibited byadministering to the animal a pharmaceutical composition of the presentinvention in an amount effective to inhibit drug transport from thetarget cells or tissues of the animal. In another embodiment of themethods of the present invention, drug resistance in an animalundergoing chemotherapy is prevented by administering to the animal apharmaceutical composition of the present invention in an amounteffective to attenuate drug resistance.

[0242] Additionally, a chemical compound of the present invention may beadministered in combination with an anticancer compound that iseffective in sensitizing drug resistant tumor cells, the amount of thecombination being effective to enhance the therapeutic efficacy of theanticancer compound. Anticancer compounds that may be suitable include,for example, dihydropyridines, thioxanthenes, phenothiazines,cyclosporins, acridonecarboxamides, verapamil, cyclosporin A, PSC 833,tamoxifen, quinidine, quinine, bepridil, ketoconazole, megestrolacetate, and estramustine. Other anticancer compounds that are found toinhibit drug efflux, including newly discovered anticancer compounds,are within the scope of the combinations of the present invention.

[0243] In view of the beneficial effect of reversing MDR, as produced bythe chemical compounds of the present invention, it is anticipated thatthese compounds will be useful not only for therapeutic treatmentfollowing the onset of MDR, but also for the prevention of MDR inanimals about to undergo chemotherapy for the first time. The dosagesdescribed herein will be essentially the same whether the pharmaceuticalcompositions of the present invention are being administered for thetreatment or prevention of MDR.

[0244] The chemical compounds and pharmaceutical compositions of thepresent invention may also be useful for enhancing the therapeuticefficacy of other drugs. In view of the roles of transport proteins inimpairing drug delivery to several sites within the body, thesecompounds and compositions will have utility in increasing drug deliveryto the central nervous system, the eye, the testes, the liver, theadrenal gland, the pancreas and leukocytes. Additionally, inhibition oftransport proteins in the intestine by compounds and compositions of thepresent invention will have utility in enhancing the bioavailability oforally delivered therapeutic agents. Furthermore, the compounds andcompositions of this invention may be used to enhance the therapeuticefficacy of anti-infection drugs toward organisms that are resistant tothese drugs. In each of these cases, at least one chemical compound orpharmaceutical composition of the present invention in combination withat least one therapeutic drug would be administered to an animal in anamount effective to enhance the therapeutic efficacy of the therapeuticdrug.

[0245] In one embodiment of the methods of the present invention, thetherapeutic efficacy of an antiproliferative drug in target cells ortissues of an animal is enhanced by administering to the animal apharmaceutical composition of the present invention in an amounteffective to enhance delivery of the antiproliferative drug to thetarget cells or tissues of the animal.

[0246] In another embodiment of the methods of the present invention,the therapeutic efficacy of an anti-infective agent in an animal isenhanced by administering to the animal a pharmaceutical composition ofthe present invention in an amount effective to inhibit drug transportfrom an infectious agent in the animal.

[0247] In still another embodiment of the methods of the presentinvention, the delivery of a therapeutic agent to target cells ortissues of an animal is enhanced by administering to the animal apharmaceutical composition of the present invention in an amounteffective to enhance delivery of the therapeutic agent to the targetcells or tissues of the animal. In more preferred embodiments of thesemethods, the delivery of a therapeutic agent to the brain, testes, eye,or leukocytes is enhanced.

[0248] In yet another embodiment of the methods of the presentinvention, the absorption of an orally-delivered therapeutic agent in ananimal is enhanced by administering to the animal a pharmaceuticalcomposition of the present invention in an amount effective to enhancedrug transport across the gastrointestinal tract.

[0249] The Examples, which follow, are illustrative of specificembodiments of the invention, and various uses thereof. They are setforth for explanatory purposes only, and are not to be taken as limitingthe invention.

EXAMPLE 1 Synthesis of Phenoxymethylquinoxalinone Compounds

[0250] The reagents and solvents that were used to synthesize thephenoxymethylquinoxalinone compounds of the present invention wereobtained from Aldrich, Acros, Fisher, or VWR. Reaction progress wasmonitored by analytical thin-layer chromatography (TLC). Silica gel usedin flash chromatography was 60-200 mesh. Infrared Spectra were measuredwith an Avatar 360 ESP spectrometer and are expressed in reciprocalcentimeters. ¹H NMR and ¹³C NMR spectra were obtained on a Bruker 200MHz spectrometer. Chemical shifts are reported in ppm downfield fromMe₄Si. J values are given in Hz.

[0251] A particularly preferred embodiment of thephenoxymethylquinoxalinone compounds of the present invention,2-(4-Methyl-3-oxo-3,4-dihydroquinoxalin-2-yl-methoxy)-N-phenylbenzamide,was synthesized as follows. The compound1,3-Dimethyl-1H-quinoxalin-2-one (Compound A) was prepared by dissolvingN-methyl-1,2-phenylenediamine (6.68 g, 54.7 mmol) and pyruvic acid (3.8mL, 54.7 mmol) in ethanol (230 mL) and warming the mixture to 50° C. Thecolor changed dramatically from a dark, cloudy brown to clear orange.Ethanol was evaporated and the crude product was filtered through asilica bed with CH₂Cl₂/EtOAc (1:1) to give 7.36 g of product as a yellowsolid (mp. 75-77° C., 42.3 mmol, 77.2%). FT-IR (KBr): 3075-2975 cm⁻¹(aromatic CH), 2950-2850 (aliphatic CH), 1650 (C═O), 1600 (C═N). ¹H-NMR(CDCl₃): δ7.80 (d, 1H, J=7.9 Hz), 7.52 (t, 1H, J=7.8 Hz), 7.33 (m, 2H),3.70 (s, 3H), 2.59 (s, 3H).

[0252] The compound 3-Bromomethyl-1H-1-methyl-quinoxalin-2-one (CompoundB) was prepared by dissolving Compound A (133 mg, 0.763 mmol) in CCl₄(10 mL), adding N-bromosuccinimide (144 mg, 0.809 mmol) and benzoylperoxide (0.4 mg, 0.002 mmol), and heating the mixture to reflux. After10.5 hours, thin-layer chromatography (TLC; silica, 40% EtOAc/Hex)showed the reaction to be complete. The reaction was cooled to roomtemperature and filtered through a plug of silica with 40% EtOAc/Hex.Purification of the crude product by radial chromatography (silica, 40%EtOAc/Hex) gave 71 mg of pure product (mp. 180-182° C. [dec.], 0.28mmol, 49%). FT-IR (KBr): 3100-3025 cm⁻¹ (aromatic CH), 2975-2875(aliphatic CH), 1740 (C═O), 1650 (C═N). ¹H-NMR (CDCl₃): δ7.87 (d, 1H,J=8.0 Hz), 7.61 (t, 1H, J=7.3 Hz), 7.41-7.33 (m, 2H) 4.66(s, 2H), 3.74(s, 3H). ¹³C-NMR (CDCl₃): δ155.2, 153.9, 134.0, 132.7, 131.4, 130.7,124.2, 114.0, 29.5.

[0253] The 3-(phenoxymethyl)-1H-1-methyl-quinoxalin-2-one compounds wereprepared by dissolving Compound B (100 mg, 0.395 mmol) and a specificphenol (0.395 mmol) in CHCl₃ (10 mL). A solution of NaOH (23.7 mg, 0.593mmol) and benzyltriethylammonium chloride (9 mg, 0.040 mmol) in H₂O (10mL) was added and the mixture stirred rapidly while heating to 50° C.The progress of the reaction was monitored by TLC (silica, 40%EtOAc/Hex). The mixture was then cooled to room temperature, the aqueouslayer was extracted with fresh CHCl₃ (2×10 mL), the combined chloroformextracts were washed with brine (10 mL), and the product was dried overNa₂SO₄. Evaporation of the solvent, followed by filtration through aplug of silica with 40% EtOAc/Hex yielded a crude product. Purificationby radial chromatography (silica, 40% EtOAc/Hex) yielded pure product.

[0254] A resulting pure product,2-(4-Methyl-3-oxo-3,4-dihydroquinoxalin-2-yl-methoxy)-N-phenylbenzamide,was a yellow solid (mp. 148° C. [dec.], 43%). FT-IR (KBr): 3315 cm⁻¹(amide NH), 3040 (aromatic CH), 2916 (aliphatic CH), 1656 (amide C═O),1643 (C═O), 1598 (C═N). ¹H-NMR (CDCl₃): δ8.31 (dd, 1H, J=1.8, 7.8 Hz),7.80-7.05 (m, 13H), 5.59 (s, 2H), 3.76 (s, 3H).

EXAMPLE2 Reversal of P-gp-Mediated or MRP-Mediated MDR byPhenoxymethylquinoxalinones

[0255] The ability of the phenoxymethylquinoxalinone compounds of thepresent invention to reverse P-gp-mediated or MRP-mediated MDR wasanalyzed using MCF-7 human breast carcinoma cells; NCI/ADR cells, an MDRcell line that over-expresses P-gp (Fairchild et al., 1987, Cancer Res.47:5141-48), but not MRP; and MCF-7/VP cells, a cell line that expressesMRP (Schneider et al., 1994, Cancer Res. 54:152-58), but not P-gp.

[0256] Reversal of P-gp-mediated MDR was examined by first platingNCI/ADR cells into 96-well tissue culture plates at approximately 15%confluency and incubating the cells for 24 hours to allow forattachment. The cells were then exposed to varying concentrations ofphenoxymethylquinoxalinone compounds in the absence or presence of 50 nMvinblastine for 48 hours as described previously (Smith et al., 1994,Oncology Res. 6:211-18; Smith et al., 1995, Mol. Pharmacol. 47:241-47).Cell survival was assayed using the sulforhodamine B binding assay(Skehan et al., 1990, J. Natl. Cancer Inst. 82:1107-12). The percentageof cells that died following treatment was calculated as a percentdecrease in sulforhodamine B binding as compared with control cultures.Control cultures were exposed to equivalent amounts of ethanol (as thesolvent control), which did not modulate the growth or drug-sensitivityof these cells at the doses used. Inhibition of P-gp was manifested asthe ability of the compound to enhance the cytotoxicity of vinblastinetoward NCI/ADR cells. To assess the toxicity of the compounds towarddrug-sensitive cells, the effects of the compounds on the growth ofdrug-sensitive MCF-7 cells were determined using the same methods.

[0257] Reversal of MRP-mediated MDR was examined by plating MCF-7/VPcells as described above and exposing the cells to varyingconcentrations of phenoxymethylquinoxalinone compounds in the absence orpresence of 1 nM vincristine for 48 hours. Cell survival was assayed asdescribed above. The percentage of cells that died following treatmentwas calculated as described above. Inhibition of MRP was manifested asthe ability of the compound to enhance the cytotoxicity of vincristinetoward MCF-7/VP cells.

[0258] The results obtained for twenty-two phenoxymethylquinoxalinonecompounds are shown in Table I. Tested phenoxymethylquinoxalinonecompounds were found to have an intrinsic cytotoxicity towards MCF-7cells. Cytotoxicity is expressed as the concentration ofphenoxymethylquinoxalinone compound required to kill 50% of the cells.In several cases, the maximum solubility of the compound was less thanthe IC₅₀. While toxicity toward cultured cancer cells is a typical anddesired property for drugs having utility in the treatment of cancer, itis desirable that chemosensitizing compounds have low intrinsictoxicity. The phenoxymethylquinoxalinone compounds that were examinedwere found to have low cytotoxicity, with IC₅₀ values of >20 μM, and insome cases near 100 μM (Table I).

[0259] The P-gp antagonism score was calculated by dividing the percentsurvival of NCI/ADR cells treated with the compound alone by the percentsurvival of NCI/ADR cells treated with the compound in the presence of50 nM vinblastine. Chemosensitization is indicated by a score of morethan 1.0. Several of the phenoxymethylquinoxalinone compounds that weretested demonstrated this property (Table I).

[0260] The MRP antagonism score was calculated by dividing the percentsurvival of MCF-7/VP cells treated with the compound alone by thepercent survival of MCF-7/VP cells treated with the compound in thepresence of 1 nM vincristine. Chemosensitization is indicated by a scoregreater than 1.0. None of the phenoxymethylquinoxalinone compounds thatwere tested demonstrated this property (Table I). Thus, a number of thephenoxymethylquinoxalinone compounds that were tested were found to beeffective inhibitors of P-gp, but not MRP.

[0261] Similar experiments were conducted using verapamil or one of theparticularly preferred phenoxymethylquinoxalinone compounds. FIGS. 4A-4Billustrate the antagonism of P-gp by verapamil andphenoxymethylquinoxalinone compounds and FIGS. 5A-5B illustrate the lackof antagonism of MRP1 by phenoxymethylquinoxalinone compounds.

EXAMPLE 3 Synthesis of Pyrroloquinoline Compounds

[0262] The reagents and solvents that were used to synthesize thepyrroloquinoline compounds of the present invention were obtained fromAldrich, Acros, Fisher, or VWR. Reaction progress was monitored byanalytical thin-layer chromatography (TLC). Silica gel used in flashchromatography was 60-200 mesh. Infrared Spectra were measured with aAvatar 360 ESP spectrometer and are expressed in reciprocal centimeters.¹H NMR and ¹³C NMR spectra were obtained on a Bruker 200-MHzspectrometer. The chemical shifts were reported in ppm downfield fromMe₄Si. J values are given in Hz.

[0263] Pyrroloquinoline compounds were synthesized as follows. Thecompound 1-benzyl-2, 3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-ylamine wasprepared from the cyclization of an amidine derivative,2-(1-benzyl-pyrrolidin-2-ylideneamino)benzonitrile, which wassynthesized by condensing an anthranilonitrile and1-benzyl-2-pyrrolidione. This compound was then reacted with potassiumtert-butoxide or sodium hydride and the corresponding alkyl chloride oracyl chloride (FIG. 6).

[0264] The compound 2-(1-Benzyl-pyrrolidin-2-ylideneamino)benzonitrile(Compound 24) was synthesized by mixing chloroform (25 mL),tetrahydrofuran (25 mL), 1-benzyl-2-pyrrolidinone (5.16 g, 29.4 mmol),phosphorus oxychloride (5.2 mL) and tin(IV) chloride (1.0 mL), stirringat room temperature for 1.5 hours, and adding anthranilonitrile (3.3 g,27.9 mmol) in portions. The mixture was then stirred at 50° C. for 5hours under heating and ice-water (15 mL) and 10% aqueous sodiumhydroxide solution was added to make weak alkaline. The organic solventwas removed under reduced pressure and the mixture was extracted withchloroform. The extract was dried over anhydrous sodium sulfate andcondensed under vacuum. The crude product was purified by flashchromatography (chloroform-methanol, 100:1) to yield 7.0 g (91%)Compound 24 as slightly yellow needles; mp 59-61° C.; IR (KBr): 2217,1628, 1439, 1279cm⁻¹; ¹H NMR (DMSO-d₆): δ7.06-7.69 (m, 9H), 4.83 (s,2H), 3.46 (t, 2H), 2.60 (t, 2H), 2.10 (m, 2H); ¹³C NMR (CDCl₃): δ162.8,156.3, 137.6, 133.7, 132.9, 128.7, 128.3, 127.4, 122.8, 121.7, 118.8,105.9, 48.3, 47.3, 27.7, 19.6. Anal. Calcd. for C₁₈H₁₇N₃(275.35): C,78.52; H, 6.22; N, 15.26. Found: C, 78.37; H, 6.20; N, 15.17.

[0265] The compound1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-ylamine (Compound 25)was synthesized by first cooling a solution of Compound 24 (37.6 g, 0.14mol) and tetrahydrofuran (350 mL) to −35° C. under argon atmosphere andadding a solution of hexane (110 mL) and lithiumdiisopropylamine-tetrahydrofuran complex (0.35 mol) dropwise. Thetemperature of the mixture was then gradually raised to −10° C. andice-water (30 mL) was added dropwise. Organic solvent was evaporatedunder reduced pressure and the mixture was extracted with chloroform.The combined organic extracts were dried with anhydrous sodium sulfateand condensed under vacuum. The residue was treated with ethanol (15 mL)and crystals precipitated. The precipitate was filtered, washed withcold ethanol and dried under vacuum to yield 14.6 g (39%) of Compound 25as needles; mp 174-176° C.; IR (KBr): 3411, 3116, 1654, 1502, 1350,756cm⁻¹; ¹H NMR (DMSO-d₆): δ7.01-7.93 (m, 9H), 6.05 (s, 2H), 4.60 (s,2H), 3.37 (t, 2H), 2.87 (t, 2H); ¹³C NMR (CDCl₃): δ162.7, 149.3, 144.8,138.8, 128.7, 128.2, 128.1, 127.2, 126.2, 121.8, 119.9, 117.6, 100.7,48.4, 23.3. Anal. Calcd. for C₁₈H₁₇N₃(275.35): C, 78.52; H, 6.22; N,15.26. Found: C, 78.07; H, 6.07; N, 15.08.

[0266] The compounds(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-ylamino)-acetic acidethyl ester (Compound 26),(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-(3-fluoro-benzyl)-amine(Compound 27),(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-(4-fluoro-benzyl)-amine(Compound 28), and(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-(3,5-dimethoxy-benzyl)-amine(Compound 29) were synthesized by first adding potassium tert-butoxideto a solution of Compound 25 (1 mmol) in tetrahydrofuran (15 mL) at 0°C. under nitrogen atmosphere and stirring at room temperature for 1.5hours. The reaction mixture was then added dropwise to a solution of acorresponding alkyl chloride (1 mmol) in tetrahydrofuran (10 mL) viasyringe at −5° C., warmed to room temperature, and stirred for 1.5 to 3hours. The resulting reaction mixture was poured into water (50 mL) andthe solid precipitated. The precipitate was filtered, dried undervacuum, and the crude product purified by flash silica gelchromatography (chloroform-methanol) to yield Compounds 26-29 (see TableII).

[0267] Data for Compound 26 were as follows: yield 61%; mp 132-134° C.;IR (KBr): 3410, 1745, 1620, 1502, 1215cm⁻¹; ¹H NMR (CDCl₃): δ7.16-7.72(m, 9H), 4.77 (s, 2H), 4.25 (q, 2H), 3.51 (t, 2H), 3.49 (s, 2H), 3.11(t, 2H), 1.34 (t, 3H); ¹³C NMR (CDCl₃): δ171.1, 157.4, 139.6, 137.1,135.5, 132.1, 128.8, 128.5, 128.3, 127.3, 126.5, 124.5, 121.7, 120.5,61.9, 48.7, 48.0, 26.1, 24.9, 14.6. Anal. Calcd. for C₂₂H₂₃N₃O₂(361.18): C, 73.11; H, 6.41; N, 11.63. Found: C, 73.04; H, 6.08; N,11.90.

[0268] Date for Compound 27 were as follows: yield 65%; mp 170-171° C.;IR (KBr): 3400, 3063, 1622, 1504, 1217cm⁻¹; ¹H NMR (CDCl₃): δ7.00-8.15(m, 13H), 4.73 (s, 2H), 4.19 (s, 2H), 3.21 (t, 2H), 2.45 (t, 2H); ¹³CNMR (CDCl₃): δ164.7, 162.5, 159.8, 149.8, 148.6, 137.8, 136.4, 133.5,133.4, 130.4, 130.2, 128.6, 128.4, 128.2, 127.2, 126.6, 123.6, 121.7,119.1, 115.4, 115.0, 54.5, 48.8, 47.8, 25.4. Anal. Calcd. for C₂₅H₂₂FN₃(383.46): C, 78.30; H, 5.78; N, 10.96. Found: C, 78.23; H, 5.32; N,11.21.

[0269] Data for Compound 28 were as follows: yield 80%; mp 167-169° C.;IR (KBr): 3405, 1620, 1502, 1215cm⁻¹; ¹H NMR (CDCl₃): δ6.92-8.10 (m,13H), 4.72 (s, 2H), 4.21 (s, 2H), 3.21 (t, 2H), 2.48 (t, 2H); ¹³C NMR(CDCl₃): δ165.5, 162.5, 160.6, 149.9, 148.5, 140.3, 137.8, 129.9, 128.7,128.5, 128.2, 127.2, 126.7, 124.3, 123.5, 121.8, 119.1, 115.7, 115.3,114.7, 114.2, 54.9, 48.9, 47.9, 25.5. Anal. Calcd. for C₂₅H₂₂FN₃(383.46): C, 78.30; H, 5.78; N, 10.96. Found: C, 78.73; H, 5.75; N,11.08.

[0270] Data for Compound 29 were as follows: yield 84%; mp 133-135° C.;IR (KBr): 3420, 1621, 1509, 1218cm⁻¹; ¹H NMR (CDCl₃): δ6.57-8.15 (m,12H), 4.71 (s, 2H), 4.13 (s, 2H), 3.67 (s, 6H), 3.23 (t, 2H), 2.56(t,2H); ¹³C NMR (CDCl₃): δ162.1, 160.6, 149.5, 149.0, 141.4, 139.2, 1291,128.4, 128.2, 127.2, 126.5, 123.7, 121.7, 121.5, 119.8, 106.6, 106.3,99.6, 55.6, 55.2, 48.8, 47.9, 25.5. Anal. Calcd. for C₂₇H₂₇N₃O₂(425.52): C, 76.21; H, 6.40; N, 9.87. Found: C, 76.23; H, 6.36; N, 9.50.

[0271] The compoundsN-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-acetamide(Compound 30),N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2-piperidin-1-yl-acetamide(Compound 31),N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2-phenyl-acetamide(Compound 32),N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2-fluoro-6-trifluoromethyl-benzamide(Compound 33),N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-4-fluoro-3-trifluoromethyl-benzamide(Compound 34), andN-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2,3,6-trifluoro-benzamide(Compound 35) were synthesized by adding a solution of Compound 25 (1mmol) in DMF (10 mL) dropwise to a suspension of sodium hydride (1 mmol)in DMF (20 mL) at 0° C. under nitrogen atmosphere. After 5 minutes, acorresponding acyl chloride was slowly added (over 20 minutes) to themixture via syringe at −5° C. and the reaction mixture was stirred atroom temperature for 1-4 hours (see Table II). The reaction mixture wasthen filtered through a pad of silical gel, the solvent was removedunder reduced pressure, and the residue was purified by flash silica gelchromatography (chloroform-methanol) to yield Compounds 30-35 (see TableII).

[0272] Data for Compound 30 were as follows: yield 60%; mp 176-178° C.;IR (KBr): 3435, 2959, 1712, 1665, 1507cm⁻¹; ¹H NMR (CDCl₃): δ7.27-7.73(m, 9H), 4.76 (s, 2H), 3.47 (t, 2H), 2.98 (t, 2H), 2.29 (s, 3H); ¹³C NMR(CDCl₃): δ169.5, 162.4, 149.2, 138.6, 136.2, 129.3, 129.2, 128.7, 127.9,126.4, 123.3, 121.9, 115.7, 115.3, 114.7, 114.2, 48.6, 48.5, 25.7, 23.8.Anal. Calcd. for C₂₀H₁₉N₃O (317.38): C, 75.69; H, 6.03; N, 13.24. Found:C, 75.82; H, 6.11; N, 12.94.

[0273] Data for Compound 31were as follows: yield 49%; mp 220-222° C.;IR (KBr): 3410, 1699, 1660, 1505cm⁻¹; ¹H NMR (DMSO-d₆): δ7.05-7.78 (m,9H), 4.60 (s, 2H), 4.46(s, 2H), 3.46(m, 2H), 3.10 (m, 4H), 2.86 (t, 2H),1.72 (m, 4H), 1.52 (m, 2H); ¹³C NMR (DMSO-d₆): δ168.6, 163.6, 149.6,145.9, 139.5, 129.9, 129.7, 129.5, 128.6, 126.6, 122.7, 121.9, 118.4,102.4, 60.6, 54.5, 49.5, 24.1, 23.9, 22.7. Anal. Calcd. forC₂₅H₂₈N₄O.HCl (437.02): C, 68.70; H, 6.70; N, 12.81. Found: C, 68.81; H,6.43; N, 12.76.

[0274] Data for Compound 32 were as follows: yield 52%; mp 157-159° C.;IR (KBr): 3431, 2959, 1690, 1665, 1507, 1310cm⁻¹; ¹H NMR (DMSO-d₆):δ7.29-8.37 (m, 14H), 5.17 (s, 2H), 3.93 (s, 2H), 3.77 (t, 2H), 2.97 (t,2H); ¹³C NMR (DMSO-d₆): δ169.5, 156.5, 139.4, 137.2, 136.4, 135.1,131.7, 129.9, 129.5, 129.1, 129.0, 128.8, 127.4, 125.3, 124.6, 123.6,119.9, 118.8, 51.0, 50.5, 43.1, 25.8. Anal. Calcd. for C₂₆H₂₃N₃O.H₂O(411.50): C, 75.88; H, 6.13; N, 10.21. Found: C, 76.29; H, 6.41; N,9.82.

[0275] Data for Compound 33 were as follows: yield 55%; mp 189-191° C.;IR (KBr): 3427, 2933, 1691, 1628, 1119cm⁻¹; ¹H NMR (DMSO-d₆): δ7.35-8.25(m, 12H), 5.02 (s, 2H), 3.66(t, 2H), 2.98 (t, 2H); ¹³C NMR (DMSO-d₆):δ168.5, 165.3, 164.8, 161.2, 156.4, 148.4, 138.6, 136.4, 134.5, 131.1,129.3, 128.7, 128.3, 124.1, 123.3, 122.5, 119.4, 119.1, 118.6, 116.3,99.7, 50.3, 49.8, 23.8. Anal. Calcd. for C₂₆H₁₉F₄N₃O (465.44): C, 67.09;H, 4.11; N, 9.03. Found: C, 67.45; H, 4.19; N, 9.15.

[0276] Data for Compound 34 were as follows: yield 45%; mp 195-197° C.;IR (KBr): 3435, 1691, 1626, 1375, 1118cm⁻¹; ¹H NMR (DMSO-d₆): δ7.25-8.62(m, 12H), 4.95 (s, 2H), 3.37 (t, 2H), 3.00 (t, 2H); ¹³C NMR (DMSO-d₆):δ169.0, 165.0, 164.9, 161.2, 155.4, 147.9, 138.8, 136.0, 134.3, 131.0,129.1, 128.7, 128.2, 124.1, 123.1, 122.5, 119.4, 119.1, 118.3, 116.7,99.5, 50.8, 49.5, 23.5. Anal. Calcd. for C₂₆H₁₉F₄N₃O (465.44): C, 67.09;H,4.11; N, 9.03. Found: C, 67.50; H, 4.05; N, 9.18.

[0277] Data for Compound 35 were as follows: yield 53%; mp 160-162° C.;IR (KBr): 3430, 1689, 1378, 1119cm⁻¹; ¹H NMR (DMSO-d₆): δ7.33-8.31 (m,11H), 5.14 (s, 2H), 3.84 (t, 2H), 3.13 (t, 2H); ¹³C NMR (DMSO-d₆):δ168.9, 165.3, 164.8, 161.2, 159.2, 159.1, 159.0, 138.2, 135.6, 132.3,130.0, 129.4, 129.3, 125.9, 125.6, 124.5, 120.9, 120.5, 120.2, 119.6,113.9, 113.4, 50.7, 49.8, 23.6. Anal. Calcd. for C₂₅H18F₃N₃O (433.43):C, 69.28; H, 4.19; N, 9.69. Found: C, 69.28; H, 4.07; N, 9.62.

EXAMPLE 4 Reversal of P-gp-Mediated or MRP-Mediated MDR byPyrroloquinolines

[0278] The ability of the pyrroloquinoline compounds of the presentinvention to reverse P-gp-mediated or MRP-mediated MDR was analyzed asdescribed in Example 2.

[0279] The results obtained for forty pyrroloquinoline compounds areshown in Tables III and IV. Tested pyrroloquinoline compounds were foundto have an intrinsic cytotoxicity towards MCF-7 cells. Cytotoxicity isexpressed as either the percent of MCF-7 cells killed by 10 μ/ml of thepyrroloquinoline compound (Table III) or the concentration ofpyrroloquinoline compound required to kill 50% of the cells (Table IV).Table III illustrates the wide range of toxicity of the pyrroloquinolinecompounds that were tested—the toxicity varying from 0% for Compound 62to 99% for Compounds 36 and 50. While toxicity toward cultured cancercells is a typical and desired property for drugs having utility in thetreatment of cancer, it is desirable that chemosensitizing compoundshave low intrinsic toxicity. A number of the pyrroloquinoline compoundsthat were examined were found to have low cytotoxicity (Tables III andIV).

[0280] The P-gp antagonism score was calculated by dividing the percentsurvival of NCI/ADR cells treated with the compound alone by the percentsurvival of NCI/ADR cells treated with the compound in the presence of50 nM vinblastine. Chemosensitization is indicated by a score of morethan 1.0. Several of the pyrroloquinoline compounds that were testeddemonstrated this property (Tables III and IV).

[0281] The MRP antagonism score was calculated by dividing the percentsurvival of MCF-7/VP cells treated with the compound alone by thepercent survival of MCF-7/VP cells treated with the compound in thepresence of 1 nM vincristine. Chemosensitization is indicated by a scoregreater than 1.0. While some of the pyrroloquinoline compounds that weretested demonstrated this property, several pyrroloquinoline compoundswere found to be effective inhibitors of P-gp without inhibiting theaction of MRP (Tables III and IV). For example, Compound 62 has a P-gpantagonism score of 17.8 and a MRP antagonism score of only 1.1.

EXAMPLE 5 Anti-MDR Activity of Pyrroloquinolines

[0282] Additional pyrroloquinones were synthesized and evaluated forinhibitory activity using a panel of cell lines that exhibit the MDRphenotype due to the overexpression of either P-gp or MRP1. Theabilities of these compounds to antagonize P-glycoprotein and MRP1 areshown in FIGS. 7 and 8. The P-gp antagonism score was calculated bydividing the percent survival of NCI/ADR cells treated with 50 nMvinblastine by the percent survival of NCI/ADR cells treated with thecompound in the presence of 50 nM vinblastine. The MRP1 antagonism scorewas calculated by dividing the percent survival of MCF-7/VP cellstreated with 1 nM vincristine by the percent survival of MCF-7/VP cellstreated with the compound in the presence of vincristine. Largerantagonism scores indicate increasing activity and a score of 1.0indicates no activity.

[0283] Verapamil, which is highly effective at reversing MDR in vitro,was used as a positive control in experiments examining the ability ofpyrroloquinoline compounds to antagonize P-gp. Compounds 4007 and 4008were found to be somewhat more potent than verapamil, with Compound 4008having a maximal activity equivalent to that of verapamil (FIG. 7).However, while verapamil also effectively inhibits MRP1, none of thepyrroloquinoline compounds tested were found to affect this transporter(FIG. 8). Furthermore, neither Compound 4007 nor Compound 4008 werefound to be excessively cytotoxic to the cells, thereby providing atherapeutic index of at least 10-fold. These experiments indicate thatboth Compounds 4007 and Compound 4008 are P-gp-selective antagonistswith higher potencies than the non-selective antagonist verapamil.

[0284] The specificity of Compound 4008 is illustrated in Table V. TheReversal Index (RI) was calculated by dividing the IC₅₀ in the absenceeither verapamil or Compound 4008 by the IC₅₀ in the presence of 10 μMof either verapamil or Compound 4008. Both verapamil and Compound 4008were found to enhance the cytotoxicities of Pgp-substrate drugs(including vinblastine, vincristine, and Taxol) toward cell lines thatoverexpress P-gp (i.e., NCI/ADR, P388/Adr and A498 cells). In contrast,neither compound strongly affected the toxicities of these drugs towardcell lines that do not overexpress P-gp (i.e., T24 and MCF-7), andneither compound affected the toxicities of non-P-gp substrate drugs(i.e., cisplatin and 5-fluorouracil) towards any of the cell lines.Therefore, the modulatory effects appear to be due to the inhibition ofdrug transport by P-gp. The difference in transporter selectivitybetween Compound 4008 and verapamil is also illustrated by the markedability of verapamil to enhance the toxicity of vincristine towardMRP1-overexpressing MCF7/VP cells, whereas Compound 4008 has no effecton the toxicity of this drug toward MCF7/VP cells. Additionalexperiments also indicate that Compound 4008 increases the accumulationof [³H]Taxol and [³H]vinblastine by NCI/ADR cells without affecting theaccumulation of these drugs by MCF-7 or MCF-7/VP cells.

[0285] It should be understood that the foregoing disclosure emphasizescertain specific embodiments of the invention and that all modificationsor alternatives equivalent thereto are within the spirit and scope ofthe invention as set forth in the appended claims. TABLE I Cytotoxicityand MDR Antagonism by Phenoxymethylquinoxalinones Compound R₁ R₂ IC₅₀(μM) P-gp MRP1 P-gp/MRP1 1 H CH₃ >94 3.7 1.0 3.7 2 4-fluoro CH₃  26 1.20.8 1.4 3 4-cyano CH₃ >43* 3.2 0.8 3.9 4 2,3,4,5,6-pentafluoro CH₃ >702.1 0.8 2.6 5 4-benzyloxy CH₃ >40 1.9 0.9 2.2 6 3-tert-butyl CH₃  19 4.10.9 4.5 7 3,4-dichloro CH₃ >37* 1.1 0.9 1.3 8 4-benzoyl CH₃ >67 4.7 0.94.9 9 3-methyl-4-nitro CH₃ >77 1.6 1.1 1.4 10 4-CO₂CH₃-2-OCH₃ CH₃  715.6 1.1 5.2 11 2-C(O)NH-phenyl CH₃ >32* 3.6 1.0 3.6 12 3-(dimethylamino)CH₃  57 1.1 0.9 1.1 13 ethyl 4-carboxylate CH₃ >74 3.8 0.9 4.2 143-(N-phenylamine) CH₃  25 1.3 0.9 1.5 15 2-benzyl CH₃  8.1 1.0 1.1 0.916 3-hydroxypyridine CH₃ >56 1.0 1.1 0.9 17 4-phenyl CH₃  30 2.5 0.7 3.718 2-C(O)NH-phenyl benzyl >54 12.4 0.9 13.4 19 2-benzo CH₃  20 1.0 0.91.2 20 3-benzo CH₃  40 1.2 0.9 1.3 21 3,5-dimethoxy CH₃  25 1.2 0.9 1.322 3,4-dimethoxy CH₃  28 1.1 0.9 1.2 23 3,4,5-trimethoxy CH₃  21 1.2 0.91.3

[0286] TABLE II Reaction Conditions, Yields, and Melting Points ofPyrroloquinolines Reaction Conditions Yield mp Compound Cat^(a) Time(h)(%)^(b) (° C.) 26 A 1.5 61 132-134 27 A 2 65 170-171 28 A 3 80 167-16929 A 3 84 133-135 30 B 1 60 176-178 31 B 4 49 220-222 32 B 3 52 157-15933 B 2 55 189-191 34 B 1.5 45 195-197 35 B 2 53 160-162

[0287] TABLE III Cytotoxicity and MDR Antagonism by PyrroloquinolinesPgp MRP Compound R₁ R₂ R₃ Toxicity Antagonism Antagonism 36 methyl H7-Br 94 1.3 1.6 37 methyl

12 1.6 1.0 38 methyl

22 5.6 1.0 39 methyl

39 1.8 1.4 40 methyl

28 3.2 1.2 41 methyl

30 6.0 1.2 42 methyl

51 4.1 1.2 43 methyl

50 4.2 1.3 44 methyl

21 1.7 1.4 45 methyl

29 4.7 0.9 46 methyl

99 1.0 1.0 47 methyl

58 2.4 1.0 48 butyl H 7-Br 98 1.1 1.0 49 cyclohexyl H 97 0.8 0.6 50cyclohexyl H 7-Br 99 1.0 1.0 51 phenyl H 52 2.7 1.1 52 3-chloro-benzyl

33 1.2 1.2 53 benzyl H 47 3.1 1.0 54 benzyl H 7-Br 94 1.7 1.3 55 benzylH 7-CH₃ 98 0.7 1.0 56 benzyl H 9-CH₃ 77 1.6 1.7 57 benzyl H 6,9-CH₃ 811.5 1.2 58 benzyl H 7,9-CH₃ 49 3.6 1.4 59 benzyl

45 13.0 0.99 60 benzyl

29 61 benzyl

14 14.8 0.98 62 benzyl

0 17.8 1.09 63 benzyl

21 7.5 1.07 64 benzyl

50 13.2 1.15

[0288] TABLE IV Cytotoxicity and MDR Antagonism by PyrroloquinolinesMaximum Toxicity Antagonism at IC₂₀ or less Antagonism Compound R₁ R₂IC₅₀ (μg/ml) P-gp MRP (conc. μg/ml) 4001

H 1.7 1.0 1.0  4.0 (3.1) 4002

12 0.9 0.9  8.3 (25) 4003

>25 1.2 0.7  1.7 (25) 4004

>25 1.3 0.7  1.3 (12.5) 4005

20 1.4 0.9  7.9 (25) 4006

3.5 1.1 0.9  2.3 (12.5) 4007

6 9.0 1.0 11.8 (3.1) 4008

5 10.7 0.7 17.1 (3.1) 4009

6 2.5 0.9  9.8 (3.1) 4010

9 4.9 0.9 11.3 (3.1) 4011

>25 3.1 1.0  3.1 (6.25)

[0289] TABLE V Cell Line-Specificity and Drug-Specificity of the Effectsof Compound 4008 and Verapamil EtOH Verapamil 4008 Cell Line Drug IC₅₀IC₅₀ RI IC₅₀ RI Non-Pgp Cell Lines T24 Vinblastine (nM) 1.3 ± 0.3 0.5 ±0.1 2.7 0.4 ± 0.1 3.8 Taxol (nM) 4.7 ± 0.5 3.0 ± 0.4 1.6 4.0 ± 0.6 1.2Vincristine (nM) 4.8 ± 0.2 1.3 ± 0.2 3.7 2.2 ± 0.6 1.5 Cisplatin (μM)6.7 ± 1.1 7.0 ± 0.8 1.0 5.8 ± 1.2 1.1 5-Fluorouracil (μM) 77 ± 20 48 ±6  1.6 29 ± 8  2.6 MCF-7 Vinblastine (nM) 0.4 ± 0.1 0.3 ± 0.1 1.2 0.2 ±0   1.8 Taxol (nM) 1.6 ± 0.3 1.4 ± 0.6 1.1 1.8 ± 0.1 0.9 Vincristine(nM) 0.6 ± 0.1 0.1 ± 0.1 4.6 0.4 ± 0.1 0.9 Cisplatin (μM) 16 ± 5  14 ±4  1.1 19 ± 5  0.8 5-Fluorouracil (μM) 49 ± 31 53 ± 20 0.9 30 ± 15 1.6MCF7/VP Vinblastine (nM) 0.6 ± 0.1 0.2 ± 0   2.4 0.4 ± 0.1 1.3 (MRP1)Taxol (nM) 1.8 ± 0.4 1.6 ± 0.4 1.1 2.1 ± 0.4 0.8 Vincristine (nM) 7.5 ±1.1 0.5 ± 0.2 15.0 7.3 ± 0.9 1.0 Cisplatin (μM) 8.5 ± 2.1 10.5 ± 3.2 0.8 11.3 ± 0.5  0.8 5-Fluorouracil (μM) 11 ± 1  12 ± 2  0.9 16 ± 3  0.7Pgp Cell Lines NCI/ADR Vinblastine (nM) 110 ± 17  0.6 ± 0.1 173 3.1 ±2.0 35 Taxol (nM) 2020 ± 810  19 ± 5  106 29 ± 5  70 Vincristine (nM)183 ± 14  3.7 ± 0.8 50 10.5 ± 1.1  18 Cisplatin (μM) 7.0 ± 0.9 6.3 ± 0.81.1 6.0 ± 0.5 1.2 5-Fluorouracil (μM) 181 ± 84  210 ± 99  0.9 175 ± 74 1.0 P388/ADR Vinblastine (nM) 28 ± 5  0.5 ± 0.1 61 0.5 ± 0.1 63 Taxol(nM) 1650 ± 470  5.0 ± 1.4 330 8.2 ± 2.9 202 Doxorubicin (μM) 26.7 ±10.6 0.03 ± 0.01 1000.0 0.13 ± 0.09 200 Vincristine (nM) 150 ± 24  1.3 ±0.5 112 5.0 ± 2.9 30 Cisplatin (μM) 2.1 ± 0.8 1.1 ± 0.3 2.0 1.1 ± 0.41.9 5-Fluorouracil (μM) 0.22 ± 0.04 0.30 ± 0.08 0.7 0.32 ± 0.08 0.7 A498Vinblastine (nM) 7.6 ± 2.6 0.9 ± 0.5 8.5 0.43 ± 0.12 18 Taxol (nM) 49 ±21 2.7 ± 0.5 18 7.3 ± 3.4 6.8 Vincristine (nM) 62 ± 11 1.3 ± 0.3 49 3.5± 1.1 18 Cisplatin (μM) 4.6 ± 1.0 5.4 ± 0.9 0.8 6.0 ± 1.4 0.85-Fluorouracil (μM) 9.0 ± 2.1 8.0 ± 2.8 1.1 13.0 ± 5.0  0.7

What we claim is:
 1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein R₁ is H, alkyl(C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, halogen,haloalkyl, —OH, alkoxy, hydroxyalkyl, alkanoyl, arylalkanoyl, —COOH,—CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH,—S-alkyl, —CF₃, —OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl); wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆); R₂ is H,alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, —COOH, —CONH₂,—CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH, —S-alkyl, —CF₃,—OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆alkyl); wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆); or R₂is:

wherein R₄ represents H, alkyl (C₁-C₆), halogen, haloalkyl, —OH, alkoxy,hydroxyalkyl, —SH, —S-alkyl, —NO₂, —NH₂, mono- or dialkylamino,aminoalkyl, mono- or dialkylaminoalkyl, pyrrolyl, morpholinyl,thiomorpholinyl, piperidyl, or piperazyl, heterocycloalkylalkyl, phenyl,benzyl, heteroaryl, or heteroarylalkyl; wherein each of the above isoptionally substituted with up to 5 groups that are independently alkyl(C₁-C₆), halogen, haloalkyl, —CF₃, —OCF₃, —OH, alkoxy, hydroxyalkyl,—CN, —CO₂H, —SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″ areindependently H or alkyl (C₁-C₆); R₃ is H, alkyl (C₁-C₁₅), cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, heterocycloalkylalkyl, halogen, haloalkyl, —OH,alkoxy, hydroxyalkyl, —COOH, —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆alkyl)(C₁-C₆ alkyl), —SH, —S-alkyl, —CF₃, —OCF₃, —NO₂, —NH₂, —CO₂R₈,—OC(O)R₈, carbamoyl, mono or dialkylcarbamoyl, mono- or dialkylamino,aminoalkyl, mono- or dialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl),—CSN(C₁-C₆ alkyl)(C₁-C₆ alkyl); wherein each of the above is optionallysubstituted with up to 5 groups that are independently alkyl (C₁-C₆),halogen, haloalkyl, —CF₃, —OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H,—SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″ are independently H oralkyl (C₁-C₆); R₇ is H, alkyl (C₁-C₆), alkoxy, alkoxycarbonyl,arylalkyl, or arylalkoxycarbonyl, wherein each is optionally substitutedwith up to three groups that are independently alkyl, alkoxy, —NO₂, —OH,halogen, —CN, —CF₃, or —OCF₃; and R₈ is H, alkyl, aryl, arylalkyl,cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, or heterocycloalkylalkyl; wherein each of the above isoptionally substituted with up to 5 groups that are independently alkyl(C₁-C₆), alkoxy (C₁-C₆), halogen, haloalkyl, —CF₃, —OCF₃, —OH, alkoxy,hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ andR″ are independently H or alkyl (C₁-C₆).
 2. A compound according toclaim 1, wherein R₁ is H, alkyl (C₁-C₆), alkoxy, cycloalkyl,cycloalkylalkyl, alkanoyl, benzyl, or benzoyl; wherein each of the aboveis optionally substituted with up to 5 groups that are independentlyalkyl (C₁-C₆), halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, —SH,—S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″ are independently H oralkyl (C₁-C₆); R₂ is H, alkyl (C₁-C₆), cycloalkyl, cycloalkylalkyl,arylalkyl, halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, —CONH₂,—CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), aminoalkyl, mono- ordialkylaminoalkyl, phenyl, or benzyl; wherein each of the above isoptionally substituted with up to 5 groups that are independently alkyl(C₁-C₆), halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, —SH, —S-alkyl,—NO₂, or —NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆);or R₂ is:

wherein R₄ represents H, alkyl (C₁-C₆), halogen, haloalkyl, —OH, alkoxy,hydroxyalkyl, —SH, —S-alkyl, —NO₂, —NH₂, mono- or dialkylamino,aminoalkyl, mono- or dialkylamino, pyrrolyl, piperidyl, piperazyl,phenyl, or benzyl; wherein each of the above is optionally substitutedwith up to 4 groups that are independently alkyl (C₁-C₆), halogen,haloalkyl, —OH, alkoxy, hydroxyalkyl, —SH, —S-alkyl, —NO₂, or —NR′R″,wherein R′ and R″ are independently H or alkyl (C₁-C₆); R₃ is H, alkyl(C₁-C₁₅), cycloalkyl, cycloalkylalkyl, halogen, haloalkyl, —OH, alkoxy,hydroxyalkyl, —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆alkyl), —CO₂R₈, —CF₃, —OCF₃, —NO₂, —NH₂, aminoalkyl, mono- ordialkylaminoalkyl, phenyl, or benzyl; wherein each of the above isoptionally substituted with up to 5 groups that are independently alkyl(C₁-C₆), halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, —SH, —S-alkyl,—NO₂, or —NR′R″, wherein R′ and R″ are H or alkyl (C₁-C₆); R₇ is H,alkyl (C₁-C₆), alkoxy, or benzyl, wherein each is optionally substitutedwith up to three groups that are independently alkyl, alkoxy, —NO₂, —OH,halogen, —CN, —CF₃, or —OCF₃; and R₈ is H, alkyl, aryl, arylalkyl,cycloalkyl, or cycloalkylalkyl; wherein each of the above is optionallysubstituted with up to 5 groups that are independently alkyl (C₁-C₆),alkoxy (C₁-C₆), halogen, haloalkyl, —CF₃, —OCF₃, —OH, alkoxy,hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ andR″ are independently H or alkyl (C₁-C₆).
 3. A compound according toclaim 2 of the formula:

or a pharmaceutically acceptable salt thereof, wherein, R₄ is H, alkyl(C₁-C₆), halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, —SH, —S-alkyl,—NO₂, —NH₂, mono- or dialkylamino, aminoalkyl, mono- or dialkylamino,phenyl, or benzyl; wherein each of the above is optionally substitutedwith up to 4 groups that are independently alkyl (C₁-C₆), halogen,haloalkyl, —OH, alkoxy, hydroxyalkyl, —NO₂, or —NR′R″, wherein R′ and R″are independently H or alkyl (C₁-C₆); R₃ is H, alkyl (C₁-C₄), halogen,alkoxy (C₁-C₄), —CF₃, or —OCF₃; R₅ is H, alkyl (C₁-C₄), halogen, alkoxy(C₁-C₄), —CF₃, or —OCF₃; and R₇ is H, alkyl (C₁-C₆), alkoxy, or benzyl,wherein each is optionally substituted with up to three groups that areindependently alkyl, alkoxy, —NO₂, —OH, halogen, —CN, —CF₃, or —OCF₃. 4.A compound according to claim 2 that is:(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-ylamino)-acetic acidethyl ester;(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-(3,5-dimethoxy-benzyl)-amine;N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2-piperidin-1-yl-acetamide;N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2-phenyl-acetamide;N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2-fluoro-6-trifluoromethyl-benzamide;N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-4-fluoro-3-trifluoromethyl-benzamide;N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2,3,6-trifluoro-benzamide;or pharmaceutically acceptable salts thereof.
 5. A pharmaceuticalcomposition comprising a compound of the formula:

or a pharmaceutically acceptable salt thereof; with at least onepharmaceutically acceptable carrier or excipient, wherein R₁ is H, alkyl(C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, halogen,haloalkyl, —OH, alkoxy, hydroxyalkyl, alkanoyl, arylalkanoyl, —COOH,—CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH,—S-alkyl, —CF₃, —OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl); wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆); R₂ is H,alkyl (C₁-C₁₅), cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, —COOH, —CONH₂,—CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆ alkyl), —SH, —S-alkyl, —CF₃,—OCF₃, —NO₂, —NH₂, —CO₂R₈, —OC(O)R₈, carbamoyl, mono ordialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl, —CSNH₂, —CSNH(C₁-C₆ alkyl), —CSN(C₁-C₆ alkyl)(C₁-C₆alkyl); wherein each of the above is optionally substituted with up to 5groups that are independently alkyl (C₁-C₆), halogen, haloalkyl, —CF₃,—OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or—NR′R″, wherein R′ and R″ are independently H or alkyl (C₁-C₆); or R₂is:

wherein R₄ represents H, alkyl (C₁-C₆), halogen, haloalkyl, —OH, alkoxy,hydroxyalkyl, —SH, —S-alkyl, —NO₂, —NH₂, mono- or dialkylamino,aminoalkyl, mono- or dialkylaminoalkyl, pyrrolyl, morpholinyl,thiomorpholinyl, piperidyl, piperazyl, heterocycloalkylalkyl, phenyl,benzyl, heteroaryl, or heteroarylalkyl; wherein each of the above isoptionally substituted with up to 5 groups that are independently alkyl(C₁-C₆), halogen, haloalkyl, —CF₃, —OCF₃, —OH, alkoxy, hydroxyalkyl,—CN, —CO₂H, —SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″ areindependently H or alkyl (C₁-C₆); R₃ is H, alkyl (C₁-C₁₅), cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, heterocycloalkylalkyl, halogen, haloalkyl, —OH,alkoxy, hydroxyalkyl, —COOH, —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆alkyl)(C₁-C₆ alkyl), —SH, —S-alkyl, —CF₃, —OCF₃, —NO₂, —NH₂, —CO₂R₈,—OC(O)R₈, carbamoyl, mono or dialkylcarbamoyl, mono- or dialkylamino,aminoalkyl, mono- or dialkylaminoalkyl, —CONH₂, —CONH(C₁-C₆ alkyl),—CON(C₁-C₆ alkyl)(C₁-C₆ alkyl); wherein each of the above is optionallysubstituted with up to 5 groups that are independently alkyl (C₁-C₆),halogen, haloalkyl, —CF₃, —OCF₃, —OH, alkoxy, hydroxyalkyl, —CN, —CO₂H,—SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″ are independently H oralkyl (C₁-C₆); R₇ is H, alkyl (C₁-C₆), alkoxy, alkoxycarbonyl,arylalkyl, or arylalkoxycarbonyl, wherein each is optionally substitutedwith up to three groups that are independently alkyl, alkoxy, —NO₂, —OH,halogen, —CN, —CF₃, or —OCF₃; and R₈ is H, alkyl, aryl, arylalkyl,cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, or heterocycloalkylalkyl; wherein each of the above isoptionally substituted with up to 5 groups that are independently alkyl(C₁-C₆), alkoxy (C₁-C₆), halogen, haloalkyl, —CF₃, —OCF₃, —OH, alkoxy,hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ andR″ are independently H or alkyl (C₁-C₆).
 6. A pharmaceutical compositionaccording to claim 5, wherein R₁ is H, alkyl (C₁-C₆), alkoxy,cycloalkyl, cycloalkylalkyl, alkanoyl, benzyl, or benzoyl; wherein eachof the above is optionally substituted with up to 5 groups that areindependently alkyl (C₁-C₆), halogen, haloalkyl, —OH, alkoxy,hydroxyalkyl, —SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″ areindependently H or alkyl (C₁-C₆); R₂ is H, alkyl (C₁-C₆), cycloalkyl,cycloalkylalkyl, arylalkyl, halogen, haloalkyl, —OH, alkoxy,hydroxyalkyl, —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆alkyl), aminoalkyl, mono- or dialkylaminoalkyl, phenyl, or benzyl;wherein each of the above is optionally substituted with up to 5 groupsthat are independently alkyl (C₁-C₆), halogen, haloalkyl, —OH, alkoxy,hydroxyalkyl, —SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″ areindependently H or alkyl (C₁-C₆); or R₂ is:

wherein R₄ represents H, alkyl (C₁-C₆), halogen, haloalkyl, —OH, alkoxy,hydroxyalkyl, —SH, —S-alkyl, —NO₂, —NH₂, mono- or dialkylamino,aminoalkyl, mono- or dialkylaminoalkyl, pyrrolyl, piperidyl, piperazyl,phenyl, or benzyl; wherein each of the above is optionally substitutedwith up to 5 groups that are independently alkyl (C₁-C₆), halogen,haloalkyl, —OH, alkoxy, hydroxyalkyl, —SH, —S-alkyl, —NO₂, or —NR′R″,wherein R′ and R″ are independently H or alkyl (C₁-C₆); R₃ is H, alkyl(C₁-C₁₅), cycloalkyl, cycloalkylalkyl, halogen, haloalkyl, —OH, alkoxy,hydroxyalkyl, —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)(C₁-C₆alkyl), —CO₂R₈, —CF₃, —OCF₃, —NO₂, —NH₂, aminoalkyl, mono- ordialkylaminoalkyl, phenyl, or benzyl; wherein each of the above isoptionally substituted with up to 5 groups that are independently alkyl(C₁-C₆), halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, —SH, —S-alkyl,—NO₂, or —NR′R″, wherein R′ and R″ are H or alkyl (C₁-C₆); R₇ is H,alkyl (C₁-C₆), alkoxy, or benzyl, wherein each is optionally substitutedwith up to three groups that are independently alkyl, alkoxy, —NO₂, —OH,halogen, —CN, —CF₃, or —OCF₃; and R₈ is H, alkyl, aryl, arylalkyl,cycloalkyl, or cycloalkylalkyl; wherein each of the above is optionallysubstituted with up to 5 groups that are independently alkyl (C₁-C₆),alkoxy (C₁-C₆), halogen, haloalkyl, —CF₃, —OCF₃, —OH, alkoxy,hydroxyalkyl, —CN, —CO₂H, —SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ andR″ are independently H or alkyl (C₁-C₆).
 7. A pharmaceutical compositionaccording to claim 6 of the structure:

or a pharmaceutically acceptable salt thereof; with at least onepharmaceutically acceptable carrier or excipient, wherein: R₄ representsH, alkyl (C₁-C₆), halogen, haloalkyl, —OH, alkoxy, hydroxyalkyl, —SH,—S-alkyl, —NO₂, —NH₂, mono- or dialkylamino, aminoalkyl, mono- ordialkylamino, pyrrolyl, piperidyl, piperazyl, phenyl, or benzyl; whereineach of the above is optionally substituted with up to 5 groups that areindependently alkyl (C₁-C₆), halogen, haloalkyl, —OH, alkoxy,hydroxyalkyl, —SH, —S-alkyl, —NO₂, or —NR′R″, wherein R′ and R″ areindependently H or alkyl (C₁-C₆); R₃ is H, alkyl (C₁-C₄), halogen,alkoxy (C₁-C₄), —CF₃, or —OCF₃; R₅ is H, alkyl (C₁-C₄), halogen, alkoxy(C₁-C₄), —CF₃, or —OCF₃; and R₇ is H, alkyl (C₁-C₆), alkoxy, or benzyl,wherein each is optionally substituted with up to three groups that areindependently alkyl, alkoxy, —NO₂, —OH, halogen, —CN, —CF₃, or —OCF₃. 8.A pharmaceutical composition according to claim 6 comprising(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-ylamino)-acetic acidethyl ester;(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-(3,5-dimethoxy-benzyl)-amine;N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2-piperidin-1-yl-acetamide;N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2-phenyl-acetamide;N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2-fluoro-6-trifluoromethyl-benzamide;N-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-4-fluoro-3-trifluoromethyl-benzamide;andN-(1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-yl)-2,3,6-trifluoro-benzamide;or pharmaceutically acceptable salts thereof; with at least onepharmaceutically acceptable carrier or excipient.
 9. The pharmaceuticalcomposition of any of claims 5, 6, 7, or 8, further comprising at leastone additional chemotherapeutic agent.
 10. A method for inhibiting drugtransport from target cells or tissues in an animal undergoingchemotherapy, comprising administering to the animal the pharmaceuticalcomposition of any of claims 5, 6, 7, or 8, in an amount effective toinhibit drug transport.
 11. The method of claim 8, wherein drugtransport is mediated by P-glycoprotein.
 12. A method for preventingdrug resistance in target cells or tissues in an animal undergoingchemotherapy, comprising administering to the animal the pharmaceuticalcomposition of any of claims 5, 6, 7, or 8, in an amount effective toattenuate drug resistance in the target cells or tissues of the animal.13. A method for enhancing the therapeutic efficacy of anantiproliferative drug in target cells or tissues of an animalundergoing chemotherapy, comprising administering to the animal thepharmaceutical composition of any of claims 5, 6, 7, or 8, in an amounteffective to enhance delivery of the antiproliferative drug to thetarget cells or tissues of the animal.
 14. A method for enhancing thetherapeutic efficacy of an anti-infective agent in an animal, comprisingadministering to the animal the pharmaceutical composition of any ofclaims 5, 6, 7, or 8, in an amount effective to inhibit drug transportfrom an infectious agent in the animal.
 15. A method for enhancing thedelivery of a therapeutic agent to target cells or tissues of an animal,comprising administering to the animal the pharmaceutical composition ofany of claims 5, 6, 7, or 8, in an amount effective to enhance deliveryof the therapeutic agent to the target cells or tissues of the animal.16. The method of claim 15, wherein the target cells or tissues arebrain, testes, eye, or leukocytes.
 17. A method for enhancing theabsorption of an orally-delivered therapeutic agent in target cells ortissues of an animal, comprising administering to the animal thepharmaceutical composition of any of claims 5, 6, 7, or 8, in an amounteffective to enhance drug transport across the gastrointestinal tract.